Case9: Male, 2 mo at initiation of follow up, Hispanic ancestry

HPOsFreeText: NBS C4-acylcarnitine 1.8 umol/L, Plasma C4-acylcarnitine 3.28, umol/L, in vitro probe isoC4-acylcarnitine 0.074 umol/g protein, urine C4-acylcarnitine 7.86 mmol/mol creatinine, Urine C4/C3 ratio 63

NotHPOsFreeText: normal urine isobutyrylglycine

CaseAddInfo: unremarkable clinical condition

Case9 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.233T>C (p.Met78Thr)

ClinVar: 430160

CAID: CA6372883

gnomAD: n/a

CaseAddInfo: homozygous variants, no potential splice site alterations, no data for ACADS (SCAD-deficient) gene variants

Case2: Female, 3 m at initiation of follow up, European ancestry

HPOsFreeText: NBS C4-acylcarnitine 2.5 umol/L, plasma C4-acylcarnitine 10.00 umol/L, isoC4-acylcarnitine 0.120 umol/g protein, in vitro prob C4-acylcarnitine 0.220 umol/ g protein

CaseAddInfo: no data for urine excretion, unremarkable clinical condition

Case2 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2(ACAD8):c.289G>A (p.Gly97Arg)

ClinVar: 281037

CAID: CA6372897

gnomAD: 0.0002175 (East Asian)

Variant2: NM_014384.2(ACAD8):c.455T>C (p.Met152Thr)

ClinVar: 5355

CAID: CA117433

gnomAD: 0.0001395 (European Non-Finnish)

CaseAddInfo: compound heterozygous, potential splice-site alteration on ACAD8 at Exon 3 (+3A>G), homozygous for two common ACADS (SCAD-deficient) gene variants (625G>A/625G>A) which has 22% frequency in general population and correlates with increased accumulation of butyrylcarnitine

Case38 sex unknown, Spain

CasePresentingHPOs HP:0006846, HP:0002540, HP:0001344, HP:0001332

(Acute encephalopathy, Non-ambulatory, Nonverbal, Dystonia)

HPOsFreeText Phenotype was classified as "severe," with passive or static dystonia and an inability to stand up, walk, or speak. Patient may have gone undetected by routine screens as glutarate excretion was normal and 3-hydroxyglutarate was only slightly increased.

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting GC-MS measured glutarate of 4(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 43(nv 2–14 mm/mol creatinine). In patient fibroblasts, %GCD activity was 9. Patient tested negative in glutarylcarnitine blood spot test, even under carnitine supplementation.

CaseMethod1 SSCP

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified and SSCP screened 11 exons and intron boundaries of GCDH gene. Confirmed variants with Sanger sequencing and restriction digest. The Y155H variant creates a NcoI restriction site. Thus, while the patient's DNA fragments would cleave, control fragments would not be cleaved. The R227P variant creates a NlaIV site. This would lead to cleaved patient DNA fragments and uncleaved control fragments.

Variant 1. NM_000159.3:c.463T>C(p.Tyr155His) , 2. NM_000159.3(GCDH):c.680G>C (p.Arg227Pro), compound heterozygous

ClinVar 1. n/a, 2. 2089

CAID 1. CA404317601

gnomAD 1. MAF=0.000008791(European(non-Finnish)), no homozygotes, 2. MAF= 0.0003566(European(non-Finnish)), no homozygotes

CaseAddInfo n/a

CasePMIDs see notes on previous studies

Case21 sex unknown, Spain

CasePresentingHPOs HP:0006846, HP:0002540, HP:0001344, HP:0001332

(Acute encephalopathy, Non-ambulatory, Nonverbal, Dystonia)

HPOsFreeText Phenotype was classified as "severe," with passive or static dystonia and an inability to stand up, walk, or speak. Diagnosed by routine GC-MS organic acid analysis in urine. There was high excretion of glutarate and 3-hydroxyglutarate with glutarate excretion being higher than that of 3-hydroxyglutarate.

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting GC-MS measured glutarate of 204(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 143(nv 2–14 mm/mol creatinine). In patient fibroblasts, %GCD activity was 2.

CaseMethod1 SSCP

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified and SSCP screened 11 exons and intron boundaries of GCDH gene. Confirmed variants with Sanger sequencing and restriction digest. The A195T variant destroys a BanI restriction site. Thus, while the patient's DNA fragments would not cleave, control fragments would be cleaved.

Variant 1. NM_000159.3:c.583G>A (p.Ala195Thr), 2. NM_000159.3(GCDH):c.356C>T (p.Ser119Leu), compound heterozygous

ClinVar 1. n/a, 2. 288248

CAID 1. CA404318183

gnomAD 1. not in gnomAD, 2. MAF=0.0001984(Ashkenazi Jewish), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

CaseKLE: Male, Japan, Asian

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText:

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePreviousTesting: Identified via neonatal mass screening

CaseGenotypingMethod: Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating two compound heterozygous mutations that perfectly segregate with the phenotype.

Variant1: NM_001003841.3:c.340del (L114fs*114)

CAID: CA916079859 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA916079859

gnomAD: Not in gnomAD

Variant2: NM_001003841.3:c.682_683delinsTA (p.Thr228Ter)

CAID: CA916079860 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA916079860

gnomAD: Not in gnomAD

Patient7: Male, 2yo

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 1.6 μmol l−1, IVG in urine mmol permol creatinine = 272, IVA incorp (%) = 72, Ammonium (μmol l−1) = 51, pH = 7.39, Protein intake (g kg−1 per day) = 1.5, PDI/IQ in follow-up = 93

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed with NBS at 28 days, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.706G>A

CAID: CA268780419, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268780419

gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/15-40705199-G-A

Patient14: Male, 24yo

CasePresentingHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259, HP:0001987, HP:0001941

(poor feeding, vomiting, dehydration, lethargy, coma, hyperammonemia, acidosis)

HPOsFreeText: intermittent isovaleric acidemia, C5 (DBS) = 4.3 μmol l−1, IVA incorp (%) = 12, IVG in urine mmol permol creatinine = 16594, Ammonium (μmol l−1) = 126, pH = 7.17, Protein intake (g kg−1 per day) = 0.7, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 88

CaseNotHPOs:

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: diagnosed via clinical findings at 1yo, hospitalized outside of detection period

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1-?_c.295+? (Delexons 1–3) no ClinVar or CAID

Variant2: NM_002225.4(IVD):c.1184G>A (p.Arg395Gln) listed in paper as (p.Arg395His)

CAID: CA268781747, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781747

ClinVar: 529434, https://www.ncbi.nlm.nih.gov/clinvar/variation/529434/

gnomAD: 0.00001415, http://gnomad.broadinstitute.org/variant/15-40710365-G-A

Patient11: Female, 19yo, sibling to patient 10

CasePresentingHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

HPOsFreeText: intermittent isovaleric acidemia, IVA incorp (%) = 13, IVG in urine mmol permol creatinine = 3488, Ammonium (μmol l−1) = 47 pH = 7.33, Protein intake (g kg−1 per day) = 1.0, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 85, sweaty feet odor

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Diagnosed via clinical findings at 2yo

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3(IVD):c.884T>C (p.Leu295Pro)

ClinVar: 555464, https://www.ncbi.nlm.nih.gov/clinvar/variation/555464/

gnomAD: n/a

Variant2: NM_002225.3:c.1211A>G

CAID: CA391724518, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724518

gnomAD: n/a

Patient13 Male, 9yo

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0001259, HP:0001987

(poor feeding, lethargy, coma, hyperammonemia)

HPOsFreeText: acute isovaleric acidemia, C5 (DBS) = 16.3 μmol l−1, IVA incorp (%) = 5.5, IVG in urine mmol permol creatinine = 3352, Ammonium (μmol l−1) = 606, pH = 7.26, Protein intake (g kg−1 per day) = 0.8, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 87, sweaty feet odor

CaseNotHPOs: HP:0002013, HP:0001944 (vomiting, dehydration)

NotHPOsFreeText:

CaseAddInfo: diagnosed via clinical findings at 20 days old, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.158G>C listed in clinvar as NM_002225.4(IVD):c.149G>C (p.Arg50Pro)

CAID: CA274129, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA274129

ClinVar: 188922, https://www.ncbi.nlm.nih.gov/clinvar/variation/188922/

gnomAD: 0.00001591, http://gnomad.broadinstitute.org/variant/15-40699841-G-C

Case 13 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group __

Variant1: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, homozygous, no phenotypic info, sibling (fetus) carrier for p.W203X variant

Case 16 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.217C > T (p.Arg73Ter)

ClinVar: 203825

CAID: CA312728

gnomAD: 0.00005560 (East Asian)

CaseAddInfo: proband genotype, homozygous, no phenotypic info, sibling (fetus) is a carrier of variant

Case 5 (Level 2)

**CasePreviousTesting: ** same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.626dupT (p.Thr210Aspfs*35)

ClinVar: not in ClinVar

CAID: Not in ClinGen

gnomAD: not in gnomAD

Variant2: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier for c.626dupT maternal variant

Case 6 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

Variant1: NM_015506.2(MMACHC):c.658_660delAAG (p.Lys220del)

ClinVar: 95707

CAID: CA223197

gnomAD: 0.0003071 (East Asian)

Variant2: NM_015506.2(MMACHC):c.609G > A (p.Trp203Ter)

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier for both variants

CaseAHN16.1: Australia, White

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants segregate with the disease

CasePreviousTesting: Hartnup aminoaciduria profile was confirmed by ion exchange high performance liquid chromatography;

CaseGenotypingMethod: All SLC6A19 exons and flanking introns were directly amplified and sequenced from genomic DNA.

Variant1: NM_001003841.3:c.277G>A (p.Gly93Arg)

CAID: CA3182636 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182636

gnomAD: 0.0001195, https://gnomad.broadinstitute.org/variant/5-1208935-G-A

Variant2: NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)

ClinVar: 2019 https://www.ncbi.nlm.nih.gov/clinvar/variation/2019/

gnomAD: 0.003016, https://gnomad.broadinstitute.org/variant/5-1212453-G-A

CaseBE2P3: Male, 9 days onset

CasePresentingHPOs: HP:0001399, HP:0006579, HP:0001396, HP:0004914, HP:0002240, HP:0001290, HP:0007772, HP:0000347, HP:0000218, HP:0000954, HP:0012448, HP:0001684, HP:0003265, HP:0002490, HP:0002151, HP:0003235, HP:0001897, HP:0001272, HP:0002119, HP:0001263, HP:0000733, HP:0001414, HP:0002612 (Hepatic failure, Prolonged neonatal jaundice, Cholestasis, Recurrent infantile hypoglycemia, Hepatomegaly, Generalized hypotonia, Impaired smooth pursuit, Micrognathia, High palate, Single transverse palmar crease, Delayed myelination, Secundum atrial septal defect, Neonatal hyperbilirubinemia, Increased CSF lactate, Increased serum lactate, Hypermethioninemia, Normocytic anemia, Cerebellar atrophy, Ventriculomegaly, Global developmental delay, Stereotypy, Microvesicular hepatic steatosis, Congenital hepatic fibrosis)

HPOsFreeText: Increased bile salts, Biliary stones in gallbladder, Severe intrahepatic extramedullary haematopoiesis

CaseNotHPOs: HP:0001744, HP:0000842, HP:0008163 (Splenomegaly, Hyperinsulinemia, Decreased circulating cortisol level)

NotHPOsFreeText: Abnormally coloured stools

CaseAddInfo: Parents are first cousins

CasePreviousTesting: All patients received ursodeoxycholic acid (600 mg.m−2.d−1) and fat-soluble vitamin supplementation; All patients received an enriched diet with medium chain triglycerides and dextrin maltose; Sanger sequencing of POLG, DGUOK, and TRMU in P3 revealed no pathogenic variants; Mitochondrial RC defect was considered but no anomaly was found in isolated lymphocytes and in primary culture of fibroblasts

CaseGenotypingMethod: Sanger sequencing of the ADK gene revealed a homozygous termination variant. Both parents carried this in a heterozygous state and the younger healthy brother did not carry the mutation

Variant: NM_006721.3:c.519G>A (p.Trp173Ter)

CAID: CA377397711, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_006721.3%3Ac.519G%3EA

gnomAD: Not in gnomAD

Case# Case 2, M, Chinese, 1day old Age of Onset

CasePresentingHPOs HP:0001276, HP:0000737, HP:0008344

CasePreviousTesting Tested blood aa levels with liquid chromatography-mass spectrum spectrometry, several branched chain amino acids were overly abundant. Whole exome targeted capture sequencing was applied for the mutation screening of the suspicious patients. A total of 712 genes associated with inherited metabolic diseases were selected and their coding regions were captured.

CaseMethod1 Whole Exome

CaseMethod2 Sanger

CaseGenotypingMethod validated whole exome findings with sanger and qPCR.

Variant NM_000056.3:c.523T>C

CAID CA364657780, exon1-7 del waiting on follow up

VariantEvidence in trans with massive deletion

Case2930: Female, 3 weeks diagnosis, United States

CasePresentingHPOs: HP:0003153 (Cystathioninuria)

HPOsFreeText: Elevated total homocysteine (18.2 μM/l; reference 5.1–13.9), Elevated cystathionine (11.8 μM/l; reference 0.04–0.34), Normal total cysteine (246 μmol/l; reference 203–369)

CaseNotHPOs: HP:0001270, HP:0001263, HP:0100543, HP:0030972 (Motor delay, Global developmental delay, Cognitive impairment, Abnormal systemic blood pressure)

NotHPOsFreeText: Unresponsive to B6 treatment

CaseAddInfo: Patient is compound heterozygous for these mutations, Parental testing has confirmed these variants are in trans

CasePreviousTesting: Cystathionine (Cysta), total cysteine (tCys), and total homocysteine (tHcy) panels

CaseGenotypingMethod: PCR amplification of CTH coding regions and exon-intron boundaries was performed. These fragments were sequenced and aligned with a reference to find mutations. Those found were confirmed by restriction digest of 100 controls.

Variant1: NM_001902.5:c.932C>T (p.Thr311Ile)

CAID: CA340839077 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_001902.5%3Ac.932C%3ET

gnomAD: Not in gnomAD

Variant Too Long

Variant2: NP_001893.2:p.Gly57_Gln196del

ClinVar:

gnomAD:

Case# Patient 2, male, Japanese, 11 yo diagnosis

CasePresentingHPOs HP:0002521, HP:0004923

CaseMethod1 RG-PCR

Variant NM_000320.2:c.461A>G

CAID CA356444851

VariantEvidence intronic splice variant (Fig. 4)

CaseAddInfo consanguineous parents, mother was heterozygous, patient and 2 brothers are homozygous

CasePMIDs 7444937

CaseF2P: 2 yrs report, India

CasePresentingHPOs: HP:0001010, HP:0000750, HP:0001249, HP:0006801, HP:0004923 (Hypopigmentation of the skin, Delayed speech and language development, Intellectual disability, Brisk deep tendon reflexes, Hyperphenylalaninemia)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Family is consanguinous, Parents were confirmed heterozygous, Variant may not undergo NMD however would be missing essential domains and is predicted to be null

CasePreviousTesting: Blood phenylalanine before treatment was 1619 μmol/l, Blood tyrosine before treatment was 60 μmol/l, PKU diagnosis was based on ferric chloride test on patient urine samples and detection of elevated Phenylalanine levels in blood samples by using HPLC, in addition to analysis of clinical features.

CaseGenotypingMethod: Genomic DNA was isolated from blood samples of proband and family members. PCR amplification and sequencing was used to screen for mutations. Each mutation was confirmed by bi-directional DNA sequencing.

Variant: NM_000277.3:c.1177_1178insT (p.Asn393Ilefs*2)

CAID: CA16020958 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA16020958

gnomAD: Not in gnomAD

Case5: Female, Japan, Asian

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0003798, HP:0001561, HP:0001558, HP:0100309 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Nemaline bodies, Polyhydramnios, Decreased fetal movements, Subdural hemorrhage)

HPOsFreeText: Atrophic myofibers

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Alive at 2 months

CasePreviousTesting: N/A

CaseGenotypingMethod: After LMOD3 was identified as a potential causal gene, bidirectional Sanger sequencing was performed on DNA in genetically unresolved patients using PCR amplification covering 3 exons.

Variant1: NM_198271.4:c.300_304delGACTC (p.Thr101Argfs*4)

CAID: CA913203453 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203453

gnomAD: Not in gnomAD

Variant1: NM_198271.4:c.601_602delGA (p.Asp201Glnfs*9)

CAID: CA913203454 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203454

gnomAD: Not in gnomAD

Biallelic

Case#:15, 5 months (report), Korean, female

CaseHPOs: HP:0003235, (hypermethioninemia)

CaseNotHPOsFreeText: No neurologic problems or developmental delay; no treatment or special diet.

CaseNotHPOs:

CasePreviousTesting: At 5 months and 25 months, respectively, plasma methionine 300.2, 87.7 umol (normal <50), plasma homocysteine 14.4, 5.4 umol (<15 umol)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: All nine MAT1A exons (exon I to IX) and exon–intron boundaries were amplified by polymerase chain reaction (PCR) and directly sequenced.

Variant: c.487C>T (p.Arg163Trp) (homozygous)

ClinVar: N/A

CAID: CA5576782

gnomAD: The highest population minor allele frequency in gnomAD is 0.00006152 (African); no homozygoutes in any population.

VariantEvidence: None.

CaseAddInfo: The mother is heterozygous, the father had only the wild type allele in leukocyte DNA. Biparental inheritance was proven by microsatellite analysis suggesting that either the father is mosaic or this is a de novo variant.

CasePMIDs:

Points: 0.25 points. This individual is homozygous for a missense variant in MAT1A. The highest population minor allele frequency in gnomAD is 0.00006152 (African); no homozygotes in any population. The score is reduced because no functional evidence is available to support the deleterious impact of this variant.

Biallelic

Case#: 14, Korean, female, 58 months (report)

CaseHPOs: HP:0003235, (hypermethioninemia)

CaseNotHPOsFreeText: No neurologic problems or developmental delay; no treatment or special diet.

CasePreviousTesting: At 20 days and 58 months, respectively, Plasma methionine 1352.6, 815.2 umol (normal <50), plasma homocysteine 21.1, 19.06 umol (<15 umol)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: All nine MAT1A exons (exon I to IX) and exon–intron boundaries were amplified by polymerase chain reaction (PCR) and directly sequenced.

Variant: 1) c.895C>T (p.Arg299Cys); 2) c.1005C>G (p.Tyr335X)

ClinVar: 1) 418870 2) N/A

CAID: 2) CA377360418

gnomAD: The highest population minor allele frequency in gnomAD for c.895C>T (p.Arg299Cys) is 0.0001431 (East Asian). c.1005C>G (p.Tyr335X) is not in gnomAD

VariantEvidence: When expressed in E. Coli, the variant resulted in reduction of methionine adenosyltransferase (MAT) and tripolyphosphatase (PPPase) activities to ~15% and ~20% of wild type respectively (Fernandez-Irigoyn et al, 2010, PMID 20675163; Fig 2).

CaseAddInfo: The mother is heterozygous for the nonsense variant, methionine levels are not available.

Points: 1 point. This individual and her sister, who also has hypermethioninemia, are compound heterozygous for a missense variant, p.Arg299Cys, and a nonsense variant in MAT1A (p.Tyr335X). While the nonsense variant occurs in the second to last exon of it is further than 50 bp from the 3’ end of the exon (~80 bp), and therefore should be identified by nonsense-mediated decay. The highest population minor allele frequency in gnomAD for c.895C>T (p.Arg299Cys) is 0.0001431 (East Asian). c.1005C>G (p.Tyr335X) is not in gnomAD. The score is reduced because other causes of hypermethioninemia have not been ruled out.

CaseKDC23: Male, 38 yrs onset, Korea, Asian

CasePresentingHPOs: HP:0002131, HP:0002321, HP:0001260, HP:0000640, HP:0011477, HP:0100543 (Episodic ataxia, Vertigo, Dysarthria, Gaze-evoked nystagmus, Upbeat nystagmus, Cognitive impairment)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband has no family history of disease

CasePreviousTesting: Negtive response to acetazolamide

CaseGenotypingMethod: Next-generation sequencing was perfomed on all probands with 40 candidate genes and five known EA genes.

Variant: NM_004172.5:c.952A>G (p.Thr318Ala)

CAID: CA3235581, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3235581

gnomAD: 0.002656, https://gnomad.broadinstitute.org/variant/5-36679820-A-G NOTE EXTREMELY HIGH gnomAD FREQUENCY

Patient1: Male, 6yo

CasePresentingHPOs:

HPOsFreeText: Blood C5-carnitine (μM) = 18.96, under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 10days old and asymptomatic at diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.3:c.386A>G (p.Tyr99Cys) listed in paper as (p.His100Arg)

CAID: CA391716511, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716511

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient5-1: Female, 2.5yo, sibling to patient 5-2

CasePresentingHPOs:

HPOsFreeText: under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2mo diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.347C>T (p.Ser89Phe) listed in paper as (p.Ser87Phe)

CAID: CA391716394, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716394

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient8: Group 2

CasePresentingHPOs: same as group 2

CasePreviousTesting: same as group 2

CaseGenotypingMethod: same as group 2

Variant1: NM_002225.3(IVD):c.941C>T (p.Ala314Val) listed in paper as c.932C>T (p.Ala282Val)

ClinVar: 100060, https://www.ncbi.nlm.nih.gov/clinvar/variation/100060/

gnomAD: 0.0006507, http://gnomad.broadinstitute.org/variant/15-40707653-C-T

Variant2: NM_002225.3:c.262G>T

CAID: CA391745812, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391745812

gnomAD: n/a

Case# Patient 6, Female, 8mo diagnosis

Variant NM_000320.2:c.148G>A (p.G23D)

CAID CA2868208

gnomAD 0.001332 (African)

Case14 age/gender unknown, Caucasian, Bosnia

CasePresentingHPOs HP:0001250

(Seizures)

HPOsFreeText seizure onset in neonatal period from minutes after birth until 3 weeks of age. Definite PDE: formal pyridoxine withdrawal had resulted in reoccurrence of seizures that again responded to pyridoxine.

CaseNotHPOs n/a

CasePreviousTesting post treatment testing: Pipecolic acid in plasma 2.8(nv 0.7-2.6µmol/liter), AASA in plasma 0.5(nv<0.2µmol/liter), urine AASA 1.6(nv<1mmol/molcreatinine). Normal urine PA after pyridoxine treatment.

Variant 1. NM_001182.4:c.605G>T (p.Gly202Val ), 2. NM_001182.4:c.1184T>G (p.Val395Gly), compound heterozygous

ClinVar n/a

CAID 1. CA360731073, 2. CA360723766

gnomAD neither in gnomAD

CaseAddInfo n/a

CasePMIDs n/a

Case12 age/gender unknown, Caucasian, Italy

CasePresentingHPOs HP:0001250

(Seizures)

HPOsFreeText seizure onset in neonatal period from minutes after birth until 3 weeks of age. Definite PDE: formal pyridoxine withdrawal had resulted in reoccurrence of seizures that again responded to pyridoxine.

CaseNotHPOs n/a

CasePreviousTesting post treatment testing: Pipecolic acid in plasma 5.4(nv 0.7-2.6µmol/liter), AASA in plasma 9.6(nv<0.2µmol/liter), urine AASA 24(nv<1mmol/molcreatinine). Normal urine PA after pyridoxine treatment.

Variant NM_001182.4:c.1003C>T (p.Arg335Ter), homozygous

ClinVar n/a

CAID CA126889823

gnomAD MAF= 0.0001307(South Asian), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Patient4: Male, 2.5yo

CasePresentingHPOs: HP:0002033, HP:0001254, HP:0001987, HP:0001873, HP:0002013 (poor sucking, lethargy, hyperammonaemia, thrombocytopenia, vomiting)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula along with sodium benzoate and glycine (benzoate and glycine discontinued after 1yr), elevated isovalerylglycine, C5-carnitine = 17.4 µmol/l, birth weight = 3kg, able to sit at 6mo, walked at 13mo, began to babble at 17mo, did not have bladder/bowel control until 2.5yo, current weight = 14kg, current height = 86.5cm

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: symptom onset at 5do, diagnosis at 30do via clinical presentation, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.863C>T (p.Ala288Val) listed in paper as c.872C>T (p.Ala291Val)

ClinVar: 281076, https://www.ncbi.nlm.nih.gov/clinvar/variation/281076/

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient1: Male, 4yo, Twin A, Family A (fig. 2)

CasePresentingHPOs:

HPOsFreeText: acute neonatal IVA, treated with IVA special formula, elevated isovalerylglycine in urine organic acids, C5-carnitine = 6.15 µmol/l, at 2yo stopped formula and switched to vegetarian diet with L-carnitine supplements, admitted every 3-4mo due to metabolic crisis, at 4yo began formula again along with vegetarian diet and L-carnitine supplements, sat alone at 6mo, walked alone at 1yo, spoke first word at 1yo, unremarkable systemic examination at 4yo

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3 days old via NBS (positive family history and 3 sibling deaths), consanguineous family

CasePMIDs: PMID: 24516753

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.1184G>A (p.Arg395Gln) listed in paper as c.1193G>A (p.R398Q)

ClinVar: 529434, https://www.ncbi.nlm.nih.gov/clinvar/variation/529434/

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Case1: Newborn

CasePresentingHPOs:

HPOFreeText: Identified by NBS and is healthy with normal development.

CaseNotHPOs:

CasePreviousTesting: DBS C5 carnitine 1.2, 2.5, 1.1 umol/L (ref <0.46); plasma alloisoleucine 2.6 umol/L (ref <2.1); urine C5 carnitine 84.4, 58.1, 64.8 umol/mmol creatine (ref <3.0); urine 2-EHA 36, 31, 22 U (ref <5); urine 2-MBG 36.3, 29.3, 35.2 (ref <2.3); urine 2-methylbutyric acid conjugates as R-isomer 45%, 40% (ref 43-56%).

CaseGenotypingMethod: PCR amplification and sequencing of genomic DNA (entire coding region) from patient and available family members.

Variant: 1. NM_001609.3:c.1165A>G (p.Met389Val), 2. NM_001609.3:c.848A>G (p.Tyr283Cys)

CAID: 1. CA5730948; 2. CA5730830

gnomAD: 1. East Asian 0.0005513; 2. East Asian 0.0007068

VariantEvidence:

CaseAddInfo: In trans

CasePMIDs:

Case27 6yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256, HP:0002616, HP:0006280, HP:0002583

(Lens dislocation, Mild intellectual disability, Aortic root dilation, Chronic pancreatitis, Colitis)

HPOsFreeText Patient diagnosed on the basis of presenting marfanoid features. Patient had chronic pancreatitis requiring TPN and colitis requiring colostomy. Final CT scan of patient looking like multi-infarct dementia. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS.

Variant 1. NM_000071.2:c.684C>A (p.Asn228Lys), 2. IVS11+1G>A, comp het

ClinVar 1. n/a, 2 n/a

CAID 1. CA410600617, 2. not enough info

gnomAD 1. MAF=0.00001759(European(non-Finnish)), no homozygotes, 2. n/a

CaseAddInfo n/a

CasePMIDs n/a

Family#: JU#0213, Japanese

FamilyHPOs: HP:0012026

FamilyGenotypingMethod: PCR, sequencing of the coding exons (3-11) of the OAT gene from genomic DNA

Variant: 1) c.504_505delAA (p.K169DfsX10) (mother) 2) c.1276C>T (p.R426X) (last exon) (father)

ClinVar: 1) NA; 2) 177

CAID: 1) CA913187453

gnomAD: The maximum population minor allele frequency for c.1276C>T (p.R426X) is 0.00002893 (Latino); no homozygotes in any population. c.504_505delAA is not in gnomAD.

Proband: JU#0213:II-1

CaseII-2: Female, Japanese, 4 years death

CasePresentingHPOs: HP:0001290, HP:0001263, HP:0002453, HP:0004372, HP:0001942, HP:0045011, HP:0002339, HP:0002138, HP:0002795, HP:0007695, HP:0008000, HP:0001635, HP:0001942 (Generalized hypotonia, Developmental delay, Abnormality of the globus pallidus, Lowered consciousness, Metabolic acidosis, Decreased urine bicarbonate concentration, Abnormality of the caudate nucleus, Subarachnoid hemorrhage, Abnormal respiration, Abnormal pupillary light reflex, Decreased corneal reflex, Heart failure, Metabolic acidosis)

HPOsFreeText: Her birth weight was 2714 g, She measured 44 cm (− 2.6 SD) in length, Had an occipitofrontal circumference of 32.5 cm (− 0.5 SD), Could hold her head up at 5 months and roll over at 10 months, Febrile illness at 15 months, Required ventilator support, Absence of brain activity, Auditory brainstem response audiometry showed no response

CaseNotHPOs: HP:0009782, HP:0001250, HP:0001332 (Aplasia/Hypoplasia of the biceps, Seizures, Dystonia)

NotHPOsFreeText:

CaseAddInfo: Parents are nonconsanguineous, Older sister of patient II-2 who is also homozygous for the mutation and has the disorder, Parents are confirmed heterozygous for the mutation

CasePreviousTesting: Lactate and pyruvate levels in arterial blood (16.5 mg/dL and 1.48 mg/dL, respectively; normal range: 5–20 mg/dL and 0.3–0.9 mg/dL, respectively) and cerebrospinal liquor (13.5 mg/dL and 1.12 mg/dL, respectively; normal range: 9.1–18.8 mg/dL and 0.26–1.32 mg/dL, respectively) were almost normal, Arterial blood ketone bodies, pH, pCO2, and base excess were (8700 μmol/L; normal range: < 130 μmol/L), 7.051, 6.7 mm Hg, and − 26.9 mEq/L, respectively, CSF lactate at 1.5 (< 2.0 mmol/L reference)

CaseGenotypingMethod: Whole exome analysis was performed on the parents and the proband. Afterwards, genomic DNA was extracted from peripheral blood leukocytes and targeted sequences were amplified and sequenced. All SNVs and Indels were evaluated and filtered to confirm the mutations. Afterwards, after identifying the exon 4 mutation, a DNA segment was amplified via PCR and sequenced to confirm these findings.

Variant: NM_014362.3:c.287C>A (p.Ala96Asp)

CAID: CA349896230 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_014362.3%3Ac.287C%3EA

gnomAD: Not in gnomAD

Case: Cecconi_Patient#905, male, 30 yrs old at onset of HCM

CasePresentingHPOs:

CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm (not provided for this proband); the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM. LVEF is not provided. Family history of HCM.

CaseNOTHPOs:

CaseNOTHPOSFreeText: no family history of SCD

CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

Variant: c.1655G>A p.(Gly552Asp)

ClinVarID: or CAID: CA401714383

gnomAD: This proband has a missense variant, Gly552Asp. Not present in gnomAD. Proband has a variant in another HCM gene-MYH7.

AddCaseInfo: history of heart transplant, automatic implantable cardioverter defibrillator

PreviouslyPublished: no

VariantEvidence: none

Case: Cecconi_Patient#907, male, 37 yrs old at onset of HCM

CasePresentingHPOs:

CasePresentingHPOsFreeText: In adults, a maximal LV wall thickness (LVWT) ≥15 mm (<15mm for this proband-diagnosis of borderline HCM); the maximal LVWT between 10 and 14 mm, in conjunction with other features (i.e., family history, electrocardiogram abnormalities) prompted the diagnosis of borderline HCM. LVEF of 60%

CaseNOTHPOs:

CaseNOTHPOSFreeText: family history of HCM

CasePreviousTesting: The clinical diagnosis of primary HCM was based on medical history, a physical examination and on the echocardiographic demonstration of a hypertrophied left ventricle (LV) that could not be explained by another cardiac or systemic disease.

CaseGenotypingMethod: NGS, Sanger Targeted NGS panel to simultaneously analyze a total of 19 genes encoding not only TTm proteins, but also other sarcomeric proteins and some non-sarcomeric proteins that cause HCM phenocopies. Sanger sequencing to ensure a depth of coverage >20X for each target nucleotide.

Variant: c.432-1G>T

ClinVarID: or CAID: CA401717111

gnomAD: This proband has a splice site variant, c.432-1G>T. MAF=0.00001597 in European (non-Finnish) (2/125212 alleles), total allele frequency=0.000007246. No homozygotes. gnomAD v2.1.1.

AddCaseInfo: history of ECG abnormalities

PreviouslyPublished: no

VariantEvidence: none

genotype phenotype information for probands

CaseA009-IV-1 male, unknown age, Han Chinese

CasePresentingHPOs HP:0003251, HP:0012868, HP:0012207

(male infertility, sperm tail anomaly, reduced sperm motility)

HPOsFreeText Table S1: Sperm volume: 2.1mL, sperm concentration: 34.5million/mL, progressive motility: 0.2%, motility: 7.7%, normal spermatozoa: 6.5%, absent flagella: 30.0%, short flagella: 41.5%, coiled flagella: 18.5%, angulation: 2.5%, irregular caliber: 1.0%. Semen volume and sperm concentration were normal to the standards.

CaseNotHPOs n/a

CasePreviousTesting Ejaculation disorder, erectile dysfunction, and orchiatrophy not detected. Chromosomal karyotypes were normal (46; XY) and no deletion detected in the human Y chromosome. In addition, primary ciliary dyskinesia-related symptoms of sinusitis, bronchitis, pneumonia, and otitis media were also excluded.

Variant NM_144668.5:c.799C>T(p.Arg267Ter)

ClinVar n/a

CAID CA6840411

gnomAD Maximum population minor allele frequency in gnomAD = 0.00005903 (East Asian); no homozygotes

CaseAddInfo parents unavailable for testing

CasePMIDs n/a

Case# 39

CasePresentingHPOs HP:0000508, HP:0000601, HP0001290, HP:0000717, HP:0001249 (Ptosis, Hypertelorism, Hypotonia, Autism, Intellectual disability)

HPOFreeText: axonal neuropathy

CaseNotHPOs n/a

NotHPOFreeText: n/a

CasePreviousTesting Screened for Inherited peripheral neuropathy variants, results negative.

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod n/a

Variant NM_001163435.2:c.1652T>C (p.L551P)

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

CaseAddInfo positive family history, MAF >1% in reported ExAC findings

CasePMIDs n/a

CaseF10:III-1: Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F10

CaseF5:II-2: Male, Italy

CasePresentingHPOs: HP:0001631, HP:0001634 (Atrial septal defect, Mitral valve prolapse)

CaseAddInfo: Proband for F5, 2 other family members share MVP and 5 share ASD

Family Label: Family of patient 13940

Family#previoustesting: Restriction enzyme digest to detect presence of proband mutation in family members.

Family#method1: SSCP analysis of affected exon (12)

Affected: 6

Unaffected: 6

Segregations: 5

Proband label: 13940

Variant: NC_000022.11:g.29673267A>T

CAID: CA288260

FamilyPMIDs: Short MP, Bove C, MacCollin M, Mohney T, Rames hV, Terenzio A ,Gusella J (1994). Gender differences in neurofibromatosis, type2. Neurology 44 Suppl 2 : A159.

gnomAD: not found

Patient Number: 1507278 Pt1

FamilyPresentingHPOs: HP:0001583, HP:0000666, HP:0002421, HP:0002300, HP:0008947, HP:0001257, HP:0001332, HP:0011471, HP:0000543, HP:0007015, HP:0100543, HP:0000649, HP:0006958

FamilyNotHPOs: HP:0002015

CountryOrigin: n/a

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: PLP1 mutation screening, PLP1 duplication/deletion analyses

FamilyGenotypingMethod: Nextra custom enrichment panel, trio-based WES

Affected: 1

Unaffected: 2

Segregations: consanguineous marriage

PublishedLOD: n/a

eLOD: n/a

AddSegregationInfo: consanguinity

ProbandLabel: Patient 1; II-1, male, 8 yo, dx at 2mo

Variant: NM_177400.2; p.(Lys202Asnfs*?)

CAID: CA658820948

gnomAD: n/a

FamilyAddInfo: Patient 1 born full term with no complications, disease symptoms presented at 2mo of age with nystagmus. Gastrostomy at 2 years. Required chemodenervation for dystonia. Had transitory respiratory failure or apnoeic episode at 2 years. MRI showed increased signal in anterior nucleus of thalamus, and atrophy of cerebellar vermis.

additional phenotype info for this proband scored in PMID: 19336477

Proband KH6 was 6yo at report, has the Hurler/Scheie phenotype, and has this variant but a second variant does not appear to have been detected.

Proband KH3 was 13yo at report, has the Hurler phenotype, and has this variant in compound heterozygosity with second missense variant on exon 3, but that variant is not provided.

Case#: Caciotti_Patient1

Demographics:

CasePresentingHPOs: HP:0002655, HP:0000765, HP:0002673, HP:0003311

CaseNotHPOs: HP:0008166

CasePreviousTesting:

CaseMethod1: Total urinary glycosaminoglycan assay - 0.07 nmol/17h/mg vs 40-170 typical

CaseMethod2: CNV analysis by qPCR

CaseGenotypingMethod: Single gene seq by illumina

Variant: NM_000512.4:c.463G > A & NM_000512.4:c.899-167A >G

ClinVar: 93178 & 1048484

CAID: CA221057 & CA915941057

gnomAD: 16-88904133-C-T v2 &

VariantEvidence: single gen seq, RT-PCR from primary lymphocytes shows different transcripts, WT and larger than WT, larger has 53bp insertion from intron8 between exons 8-9

CaseAddInfo:

CasePMIDs:

Case# Subject 4, female, 17yo report, European

CasePresentingHPOs HP:0001252, HP:0001263, HP:0010864, HP:0007033, HP:0000750 (Hypotonia, Global developmental delay, Severe intellectual disability, Cerebellar dysplasia, Speech delay

HPOFreeText: hemispheric cerebellar dysplasia with abnormal lobule and fissure orientation in the inferior hemispheres(5 years); severe intellectual disability/speech delay(13 years)

CaseNotHPOs HP:0011968, HP:0012372, HP:0000453, HP:0001627, HP:0000077, HP:0002650 (Poor feeding, Abnormal eye morphology, Choanal atresia, Congenital heart defects, Renal anomaly, Scoliosis)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4303C>T(p.His1435Tyr), de novo

ClinVar n/a

CAID CA338168785

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case# Subject 3, male, 21yo report, European

CasePresentingHPOs HP:0030842, HP:0001631, HP:0001263, HP:0001249, HP:0001252, HP:0001251, HP:0000722, HP:0002474, HP:0001488, HP:0000565, HP:0010535, HP:0002650, HP:0002079, HP:0002363, HP:0000961, HP:0000733, HP:0002058, HP:0000490, HP:0000218, HP:0001222, HP:0001795 (Choking episodes, Atrial septal defect, Developmental delay, Intellectual disability, Hypotonia, Ataxia, OCD, Expressive language deficit, Bilateral ptosis, Esotropia, Sleep apnea, Scoliosis, Thin corpus callosum, Cyanosis, Stereotypy, Myopathic facies, Deep set eyes, High-arched palate, Spatulate thumbs, Hyperconvex nails

HPOFreeText: Choking episodes and atrial septal defect in infancy; recurrent cyanosis, mild hypotonia, ataxia, scoliosis, bilateral ptosis, esotropia, developmental delay and OCD (7 years); sleep apnea, throbbing headaches, thin corpus callosum, flattening of braistem, thin rim of sella, chronic right temporal membrane perforation and mild left sensorineural hearing loss(8 years); repetitive hand movements, limited speech, elongated/myopathic face/midfacial retraction, bilateral ptosis, deep-set eyes, high arched palate, spatulate thumbs and finger/toenail hyperconvexity(19 years).

CaseNotHPOs HP:0012372, HP:0000453, , HP:0000077 (Abnormal eye morphology, Choanal atresia, Renal anomaly)

CasePreviousTesting Reduced succinate cytochrome c reductaseactivity (19%), NADH and NADH cytochrome c activity were 40% of control.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.4300T>C(p.Ser1434Pro), de novo

ClinVar n/a

CAID CA338168793

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Case#: Patients 2 (male), 4 (male), and 5 (female). Kuwait. Onset between 1wk-3mo.

DiseaseAssertion: MPS I Hurler

FamilyInfo: Patients are from the same extended pedigree (family in Kuwait)

CasePresentingHPOs: α-L-iduronidase activity= 3.73 umol/g/hr (normal range 10–50) after commencing ERT. ERT for 9 wks. Congestive cardiac failure. LV fractional shortening=10%. LV ejection fraction=29%. HSCT at 17mo. α-L-iduronidase activity= 11.24 umol/g/hr (normal range 10–50) at follow up. GAG= 31.3 after transplant. Enzyme replacement therapy results in a significant reduction in urine GAGs (either total or heparan sulfate)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod:

PreviouslyPublished: n/a

Variant: Arg628Ter homozygous. Proband was homozygous for this variant. 0 points (maximum for homozygous cases has already been reached)

ClinVar: 550421

CAID: CA2802462

SupplementalData: n/a

Case# Subject 8, male, 10yo, European

CasePresentingHPOs HP:0011968, HP:0002033, HP:0002360, HP:0002020, HP:0011848, HP:0000483, HP:0000349, HP:0000494, HP:0011230, HP:0000347, HP:0000691, HP:0003186, HP:0200055, HP:0004209, HP:0010862, HP:0000750, HP:0000729, HP:0007018, (Poor feeding, Poor suck, Difficulty sleeping, Gastroesophageal reflux, Abnormal colic, Astigmatism, Widow's peak, Downslanted palpebral fissures, Laterally extended eyebrow, Micrognathia, Microdontia, Small hands, 5th finger clinodactyly, Fine motor delay, Speech delay, Autisim spectrum disorder, ADHD

HPOFreeText: Poor latch and suck, narrow dental arches, small lower arch teeth and other phenotypes reported postnatally. Fine motor delay, speech delay, autistic spectrum, and ADHD reported at 11 months. Brain MRI normal.

CaseNotHPOs HP:0001250, HP:0001252, HP:0000708, HP:0001285, HP:0001273, HP:0006808, HP:0002334, HP:0002119, HP:0007361, HP:0025100, HP:0030301, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0000047, HP:0000028, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0004322, HP:0000256, HP:0000252, HP:0011328, HP:0002007, HP:0000325, HP:0000601, HP:0000316, HP:0000582, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000187, HP:0000218, HP:0002557, HP:0011297, HP:0001792, HP:0010490, HP:0004532, HP:0000957, (Seizures, Hypotonia, Behavioral problems, Spastic quadriparesis, Abnormal Corpus Callosum, Cerebral hypomyelination, Abnormality of cerebellar vermis, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Abnormality of the anterior commissure, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Hypospadias, Cryptorchidism, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Short stature, Macrocephaly, Microcephaly, Fontanel abnormality, Frontal bossing, Triangular face, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Broad alveolar ridges, High-arched palate, Small nipples, Digital Anomalies, Nail hypoplasia, Abnormal palmar creases, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger

Variant NM_012102.3(RERE):c.1104delA, (p.Leu369Cysfs∗16)

CAID CA658820843

gnomAD n/a

VariantEvidence n/a

CaseAddInfo No paternal DNA to prove de novo status, variant suspected to trigger NMD

CasePMIDs n/a

Case# Subject 7, male, 11yo, Dutch

CasePresentingHPOs HP:0410030, HP:0001263, HP:0001252, HP:0000494, HP:0000954, HP:0007018, HP:0001256, HP:0001273, HP:0030301, HP:0006808, HP:0011968, HP:0004322, HP:0000252 (Cleft lip, Developmental delay, Hypotonia, Down-slanting palpebral fissures, Single palmar crease, ADHD, Mild intellectual disability, Abnormal Corpus Callosum, Abnormality of the anterior commissure, Cerebral hypomyelination, Poor feeding, Short Stature, Microcephaly)

HPOFreeText: Phenotypes recorded postnatally. Brain MRI at 7 years showed phenotypes including small anterior commissure and blunting of rostrum.

CaseNotHPOs HP:0001250, HP:0000708, HP:0001285, HP:0002334, HP:0002119, HP:0007361, HP:0025100, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0000047, HP:0000028, HP:0001159, HP:0001385, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0000256, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0045025, HP:0000286, HP:0000490, HP:0000598, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Seizures, Behavioral problems, Spastic quadriparesis, Abnormality of cerebellar vermis, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies, Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Hypospadias, Cryptorchidism, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Macrocephaly, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Small palpebral fissures, Epicanthal folds, Deeply set eyes, Abnormal ears, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Digital Anomalies, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting Tested negative for presence of de novo c.3382_3383delGA variant in ANKRD11 that twin sister had.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with sanger sequencing in patient and parents

Variant NM_012102.3:c.1411G>A(p.Val471Ile), de novo

ClinVar n/a

CAID CA571729

gnomAD 0.0001824(other), 0.00002032(total)

VariantEvidence n/a

CaseAddInfo Compound heterozygous for a frameshift and missense variant in FSIP2, encodes a sperm flagellum protein and is not currently associated with a human disease. Healthy older sister, but twin sister has KBG syndrome brought on by de novo deletion variant in ANKRD11 gene.

CasePMIDs n/a

Case# Subject 6, female, 6yo, Northern European/Hispanic

CasePresentingHPOs HP:0001263, HP:0001252, HP:0002938, HP:0000256, HP:0000325, HP:0000316, HP:0045075, HP:0011229, HP:0000368, HP:0000463, HP:0000319, HP:0012170, HP:0012168, HP:0001270, HP:0000750, HP:0000708, HP:0002311, HP:0000316, HP:0200055, HP:0011297 (Global developmental delay, Hypotonia, Lumbar lordosis, Macrocephaly, Triangular face, Sparse eyebrows, Broad eyebrows, Low-set-posteriorly rotated ears, Anteverted nares, Flat philtrum, Nail biting, Head bainging, Motor delay, Speech delay, Behavioral problems, Diifficulties in Coordination, Hypertelorism, Small hands, Digital anomalies)

HPOFreeText: Speech and motor delay noted at 2 years. Mildly flattened philtrum and remaining phenotypes presented postnatally.

CaseNotHPOs HP:0001250, HP:0001285, HP:0007018, HP:0011968, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002020, HP:0002247, HP:0001734, HP:0002021, HP:0000076, HP:0000107, HP:0001159, HP:0001385, HP:0002650, HP:0001511, HP:0000098, HP:0004322, HP:0000252, HP:0011328, HP:0002007, HP:0000601, HP:0000582, HP:0000494, HP:0045025, HP:0000286, HP:0000490, HP:0004467, HP:0000414, HP:0012471, HP:0000160, HP:0000221, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0011297, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Seizures, Spastic quadriparesis, ADHD, Poor feeding, Coloboma, Optic Atrophy, Microphthalmia, Peter's anomaly, Iris abnormality, Blepharophimosis, Senseorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidneys, Syndactyly, Hip dysplasia, Scoliosis, Intrauterine growth retardation, Tall stature, Short stature, Microcephaly, Fontanel abnormality, Frontal bossing, Hypotelorism, Upslanted palpebral fissures, Downslanted palpebral fissures, small palpebral fissures, Epicanthus, Deep set eyes, Preauricular pits, Bulbous nose, Full lips, Small mouth, Furrowed tongue, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipple, Inverted nipples, Small hands, Clinodactyly of the 5th finger, Digital anomalies, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Cafe-au-lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmer with sanger

Variant NM_012102.3:c.3122delC(p.Pro1041Lysfs∗40)

ClinVar n/a

CAID CA658820831

gnomAD n/a

VariantEvidence n/a

CaseAddInfo unknown if de novo like the rest, no parent testing. Family history of intellectual disability and mental illness also suggests it may not be de novo. Speculated that due to deletion being in exon 17 or 21 that NMD will occur.

CasePMIDs n/a

Case# Subject 4, female, 9yo, Northern European

CasePresentingHPOs HP:0001252, HP:0002342, HP:0001250, HP:0001999, HP:0002020, HP:0001385, HP:0000076, HP:0002079, HP:0001320, HP:0006808, HP:0001943, HP:0005968, HP:0000490, HP:0000286, HP:0000356, HP:0000221, HP:0010490, HP:0011304, HP:0001156, HP:0000708, (Hypotonia, Moderate intellectual disability, Seizures, Dysmorphic facies, Gastroesophageal reflux, Hip dysplasia, Vesicoureteral reflux, Thin corpus callosum, Cerebellar vermis hypoplasia, Cerebral hypomyelination, Hypoglycemia, Temperature instability, Deep set eyes, Epicanthus, Auricle abnormality, Furrowed tongue, Abnormal palmar creases, broad thumbs, Brachydactyly, Behavioral problems)

HPOFreeText: Fleshy auricles, deep furrow in posterior third of tongue, bilateral single palmar creases, mild brachydactyly, developmental hip dysplasia, severe vesicoureteral reflux, severe behavioral issues and other phenotypes are postnatal. Brain MRI results including diminished cerebellar vermis with deep fissures at 1 year of age.

CaseNotHPOs HP:0001285, HP:0007018, HP:0011968, HP:0002119, HP:0007361, HP:0025100, HP:0030301, HP:0012448, HP:0000589, HP:0000648, HP:0000568, HP:0000659, HP:0000525, HP:0000581, HP:0000407, HP:0000453, HP:0410030, HP:0001629, HP:0001655, HP:0001643, HP:0010772, HP:0002247, HP:0001734, HP:0002021, HP:0000107, HP:0001159, HP:0002650, HP:0002938, HP:0001511, HP:0000098, HP:0004322, HP:0000256, HP:0000252, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0000494, HP:0045025, HP:0004467, HP:0000414, HP:0000463, HP:0000319, HP:0012471, HP:0000160, HP:0000164, HP:0000187, HP:0000218, HP:0000347, HP:0002557, HP:0003186, HP:0200055, HP:0004209, HP:0001792, HP:0000349, HP:0004532, HP:0000957 (Spastic quadriparesis, ADHD, Poor feeding, Ventriculomegaly, Abnormality of the pons, Abnormal morphology of the hippocampus, Abnormality of the anterior commissure, Delayed myelination, Coloboma, Optic atrophy, Microphthalmia, Peter's anomaly, Iris anomalies,Blepharophimosis, Sensorineural hearing loss, Choanal atresia, Cleft lip, Ventricular septal defect, Patent foramen ovale, Patent ductus arteriosus, Anomalous pulmonary venous return, Duodenal atresia, Annular pancreas, Pyloric stenosis, Cystic kidney, Syndactyly, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Tall stature, Short stature, Macrocephaly, Microcephaly, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Down-slanting palpebral fissures, Small palpebral fissures, Preauricular pits, Bulbous nose, Anteverted nares, Flat philtrum, Full lips, Small mouth, Abnormal teeth, Broad alveolar ridges, High-arched palate, Micrognathia, Small nipples, Inverted nipples, Small hands, 5th finger clinodactyly, Nail hypoplasia, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with Sanger in pateint and parents

Variant NM_012102.3:c.4293C>G(p.His1431Gln), de novo

ClinVar n/a

CAID CA338168808

gnomAD n/a

VariantEvidence n/a

CaseAddInfo mosaic, de novo SCN2A missense variant. SCN2A associated with 613721 and 607745

CasePMIDs n/a

This paper evaluated factors shaping the outcome of readthrough, namely the nucleotide and protein context, with the latter being pivotal to produce functional full-length proteins. This variant was mentioned as a MPS I-H nonsense mutation, but no new case or experimental information.

Case3: Female, Italy, 7 yrs report

CasePresentingHPOs: HP:0003798, HP:0003325, HP:0001270, HP:0002093, HP:0002650, HP:0002355, HP:0003324, HP:0001283, HP:0003306 (Nemaline bodies, Limb-girdle muscle weakness, Motor delay, Respiratory impairment, Scoliosis, Difficulty walking, Generalized muscle weakness, Bulbar palsy, Spinal rigidity)

HPOsFreeText: Semi-solid diet

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001627, HP:0000602, HP:0001557, HP:0001290 (Muscular dystrophy, Myofibrillar myopathy, Cardiac abnormality, Ophthalmoplegia, Prenatal movement abnormality, Hypotonia)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed, Variant 2 creates a new splicing donor site and activates an upstream acceptor site which partially expresses intron 125 and causes a premature termination codon

CasePreviousTesting: ACTA1, TPM2 and TPM3 mutations were ruled out via amplification and direct sequencing

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes or fibroblasts. 183 exons of NEB, the relative introns, and the full promoter region was captured via litigation-mediated PCR and high-throughput sequencing of resulting fragments. These were then aligned and filtered for inheritance and pathogenicity. Variants were evaluated for amino acid conservation and confirmed by Sanger sequencing.

Variant1: NM_001271208.2:c.24559C>T (p.Arg8187Ter)

ClinVar: 496135 https://www.ncbi.nlm.nih.gov/clinvar/variation/496135/

gnomAD: Not in gnomAD

Variant2: NM_001271208.1:c.19429-381_19429-379delinsA (p.=)

CAID: CA913203565 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203565

gnomAD: Not in gnomAD

Case2: Male, Italy, Birth onset

CasePresentingHPOs: HP:0003798, HP:0002033, HP:0003325, HP:0001558, HP:0001270, HP:0002093, HP:0000194, HP:0006830, HP:0003701, HP:0002650, HP:0003458 (Nemaline bodies, Poor suck, Limb-girdle muscle weakness, Decreased fetal movement, Motor delay, Respiratory impairment, Open mouth, Congenital hypotonia, Proximal muscle weakness, Scoliosis, EMG: myopathic abnormalities)

HPOsFreeText: Wheelchair dependent

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001627, HP:0000602, HP:0001283, HP:0003306 (Muscular dystrophy, Myofibrillar myopathy, Cardiac abnormality, Ophthalmoplegia, Bulbar palsy, Spinal rigidity)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed

CasePreviousTesting: ACTA1, TPM2 and TPM3 mutations were ruled out via amplification and direct sequencing

CaseGenotypingMethod: Genomic DNA was extracted from peripheral blood leukocytes or fibroblasts. 183 exons of NEB, the relative introns, and the full promoter region was captured via litigation-mediated PCR and high-throughput sequencing of resulting fragments. These were then aligned and filtered for inheritance and pathogenicity. Variants were evaluated for amino acid conservation and confirmed by Sanger sequencing.

Variant1: NM_001164507.1:c.17737-2A>T (p.=)

CAID: CA348804839 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.17737-2A%3ET

gnomAD: Not in gnomAD

Variant2: NM_001271208.1:c.21423del (p.Lys7141Asnfs*23)

CAID: CA913203564 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203564

gnomAD: Not in gnomAD

Case: Family B Proband BII-3, male, Arabic, Israeli, 19yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0002619, HP:0002240, HP:0001629, HP:0000365, HP:0007380

CasePresentingHPOsFreeText: Dilated scleral vessels, MRI of the lower limbs demonstrated severe, symmetric, diffuse infiltration of the subcutaneous fat of the lower limbs, showing low signal in T1 and high signal intensity in T2 and fat suppressed–weighted images.

CaseNOTHPOs: HP:0008064, HP:0000054, HP:0000520, HP:0012385

CaseNOTHPOSFreeText: scrotal masses

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3

Variant: G427S homozygous

ClinVarID: or CAID: 563/CA114349

gnomAD: The missense variant G427S is present in gnomAD v4.0.0 with a MAF=0.00005339 (4/74926 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: parents were consanguineous, heterozygous. brother (BII-4) is also genotype/phenotype +

PreviouslyPublished: PMID: 18410979

VariantEvidence: Functional studies in Xenopus oocytes demonstrated that G427S results in a total loss of transport activity (Kang et al. 2010; PMID: 20595384).

Case: Family F Proband FII-6, female, Arabic, Israeli, 27yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0002619, HP:0000520, HP:0007380, HP:0100324, HP:0100727

CasePresentingHPOsFreeText: dilated scleral vessels

CaseNOTHPOs: HP:0008064, HP:0001433, HP:0011025, HP:0000365, HP:0012385

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of AIFM2, ADAMTS14, EIF4EBP2, C10ORF54, PPA1, H2AFY2, LRRC20, NODAL, PRF1, TYSND1, SAR1A, PSAP, NPFFR1, and C10ORF27

CaseGenotypingMethod: microarray, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

gnomAD: The missense variant G437R is present in gnomAD v4.0.0 with a MAF=0.00006666 (4/60002 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous parents, not genotyped. brother (FII-5) is het and unaffected.

PreviouslyPublished: PMID: 18410979

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the G437R mutation in Xenopus oocytes and observed transport activity that was approximately half that of wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated accelerated turnover of the G437R mutant compared to wildtype, suggesting decreased stability.

Database information for this variant was compiled on supplementary table s7, but no new case or experimental data.

this variant is mentioned but only as a variant from infants diagnosed through NBS for MPS1, does not appear to have been confirmed so no functional studies were performed- VUS defined by ACMG. no case level or experimental evidence provided.

NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

ClinVar 224316

CAID CA2520544

gnomAD 0.0003508(Latino), 0.0001121(Total)

This paper was listed in ClinVar, but only because it affects another residue (p.Ser633Leu) downstream which was mentioned in this paper.

Family#: RW kindred

PresentingHPOs: Heterozygotes (n = 14) had 44% normal level total cholesterol, 67% normal level LDL cholesterol, and 67% normal level apoB-100 concentrations compared with unaffected family members (n = 20), and significant mean increases in the liver enzymes alanine aminotransferase (3.8 times), aspartate aminotransferase (1.6 times), and γ-glutamyltransferase (3.0 times), and intermediate levels of serum α–tocopherol. No family member had the apoε2 isoform, ruling out this variant as a possible contributor to hypolipoproteinemia.

CountryOrigin: Lebanon (Christian)

Family#Method1: PCR

Family#Method2: Sanger sequencing

Family#GenotypingMethod: “DNA sequence analysis of the entire human APOB gene”

Affected: 2 homozygotes, 14 heterozygotes

Unaffected: 20 (i.e. homozygous normal)

PublishedLOD: 9.63 at 0% recombination fraction (for biochemical, semi-dominant phenotype)

ProbandLabel: Subject III:6

Variant: NM_000384.2:c.1468C>T (p. Arg490Trp)

ClinVar: N/A

CAID: CA053659

gnomAD: 0.00001759 (European non-Finnish)

FamilyPMIDs: PMID 8412898 (previous publication with analysis of fewer family members)

CaseIV-3: Female, 5 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970 (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -3.33 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is asserted de novo and confirmed with parental testing, Variant is a splice donor-site mutation that skips exon 14

CasePreviousTesting: Calcium levels (9.4 mg/dL), Decreased serum phosphate levels (2.0 mg/dL; reference 3.7-5.6), Elevated serum ALP (559 IU/L; reference 90-325), 25OHD3 levels (28.3 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (138 ng/L), TPR levels (79.6), Decreased TmP/GFR levels (1.59; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1586+2T>G

CAID: CA412575011 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.1586%2B2T%3EG

gnomAD: Not in gnomAD

CaseXIV-3: Female, 2.7 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970 (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -2.01 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Proband's mother shares the mutation and disease, Variant is at a splice donor site in intron 12

CasePreviousTesting: Calcium levels (9.4 mg/dL), Decreased serum phosphate levels (2.2 mg/dL; reference 3.8-6.5), Elevated serum ALP (364 IU/L; reference 90-325), 25OHD3 levels (27 ng/ml), PTH levels (49 ng/L), TPR levels (75), Decreased TmP/GFR levels (1.65; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1404+1del

CAID: CA913187413 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187413

gnomAD: Not in gnomAD

CaseIX-3: Male, 2.1 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0002970 (Hypophosphatemic rickets, Genu varum)

HPOsFreeText: -0.75 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Proband is hemizyogus for this mutation, Variant is a splice donor site at intron 4

CasePreviousTesting: Calcium levels (10.1 mg/dL), Decreased serum phosphate levels (2.6 mg/dL; reference 3.8-6.5), Elevated serum ALP (827 IU/L; reference 90-325), 25OHD3 levels (32.3 ng/ml), PTH levels (107.1 ng/L), TPR levels (74), Decreased TmP/GFR levels (1.92; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.436+1G>T

CAID: CA412571215 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.436%2B1G%3ET

gnomAD: Not in gnomAD

CaseXV-3: Female, 3.3 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0004322, HP:0002970 (Hypophosphatemic rickets, Short stature, Genu varum)

HPOsFreeText: -3.04 standard deviation score

CaseNotHPOs: HP:0000083, HP:0002024, HP:0001947 (Renal failure, Malabsorption, Renal tubular acidosis)

NotHPOsFreeText: Other tubulopathies that cause secondary hypophosphatemia, Vitamin D-dependent rickets type 1 and 2

CaseAddInfo: Variant is de novo and is confirmed by parental testing

CasePreviousTesting: Calcium levels (9.4 mg/dL), Decreased serum phosphate levels (2.9 mg/dL; reference 3.8-6.5), Elevated serum ALP (677 IU/L; reference 90-325), 25OHD3 levels (107 ng/ml), 1,25(OH)2D3 levels (54.2 pg/mL), PTH levels (79.3 ng/L), TPR levels (83.4), Decreased TmP/GFR levels (2.8; reference 2.9-6.1)

CaseGenotypingMethod: Genomic DNA was isolated from peripheral blood leukocytes, amplified, and directly sequenced in all the coding exons and intron-exon boundaries of PHEX. If no mutations were found, FGF23 followed by consecutive analysis of DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1 was performed. Significance of found mutations was predicted by computational programs and sorted.

Variant: NM_000444.5:c.1206del (p.Gln402Hisfs*6)

CAID: CA913187414 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187414

gnomAD: Not in gnomAD

Patient: P13

Variant: c.550G > T (p.Gly184Trp)

CAID: CA380695715

Functional effect: N/A

Patient: ID396

Variant: c.305_317delCCACCCAACCAACnew p.Pro102Tyrfs*41

ClinVarID/CAID: 1460243

Functional effect: Monoallelic expression of full-length allele (wt only)

Patient: ID26

Variant: c.1225_1249 + 19del (p.Met409Asnfs*14)

CAID: CA2580612035

Functional effect: Normal exon inclusion (band B) *, exon 7 skipping (band C), use of cryptic splice site: c.1249 + 64; use of cryptic splice site: c.1249 + 67; use of cryptic splice site: c.1249 + 137 (band A). Observed in blood.

Patient: ID266

Variant: c.685delG

CAID: CA2580612031

Functional effect: Normal exon inclusion (band A) *, exon 4 skipping (band B), exon 4 + 5 skipping. Observed in blood.

Cases were previously reported in PMID: 15521993.

Case: Individual 10, female, AOR= 5 years

CasePresentingHPOs: HP:0000252, HP:0001256, HP:0008935, HP:0002360, HP:0000736, HP:0012434, HP:0000712, HP:0012171, HP:0000490, HP:0030820, HP:0000431, HP:0004467, HP:0000218, HP:0010296, HP:0001010

CasePresentingHPOText: Began walking at 15 months, no notation on speech.

CaseNOTHPOs: HP:0001250, HP:0002719, HP:0000924, HP:0000202, HP:0001155, HP:0001760, HP:0000478, HP:0002719

CasePreviousTesting: No previous testing

CaseGenotypingMethod: Trio-WES.

Variant: hg19:chr2: g.4806607 8_4806607 9del, c.506_507del, p.(Ser169Leufs9) OR* NM_001190274.1:c.506_507del

CA ID: CA658820928

de novo

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The Ser169Leufs*9 mutation causes a frameshift mutation and premature stop codon. The mutation is in exon 4 and thus removes part of the F-BOX, all three CASH domains and the zinc-finger UBR region, thus it should act as a loss of function variation. No functional assays or variant evidence was provided.

Case: Individual 14, male, AOR= 9 years 10 months

CasePresentingHPOs: HP:0001263, HP:0001344, HP:0010864, HP:0001290, HP:0000739, HP:0000718, HP:0000637, HP:0000411, HP:0002019

CasePresentingHPOText: Began walking 4y.o., currently no speech. Noted as having NAD under abnormalities of the hand and feet.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0002360, HP:0000202, HP:0000924, HP:0002719

CaseNOTtextHPO:

CasePreviousTesting:

CaseGenotypingMethod: Trio-WES performed through the DDD consortium, 2017 PMID:PMID: 28135719.

Variant: g19:chr2: g.4804051 7C>T, c.2084-1G>A, p.(?) OR NM_001190274.1:c.2084-1G>A

CA ID: CA346763489

de novo

gnomAD: n/a

AddCaseInfo:

VariantEvidence: The c.2084−1G>A mutation is most likely a splice site mutation. The mutation arises in exon 18 (Intron 18?), and likely would disrupt exon 18 splicing. Exon 18 is upstream of the third CASH domain, which regulates substrate recognition. No functional assays or variant evidence was provided, so I have downgraded the score.

Case: Individual 4, male, AOR= 8 yo

CasePresentingHPOs:  HP:0001518, HP:0004322, HP:0000252, HP:0001270, HP:0011344, HP:0002187HP:0000750, HP:0002069, HP:0002121, HP:0006829, HP:0100023, HP:0000735, HP:0000248, HP:0001357, HP:0000490, HP:0011229, HP:0000527, HP:0045025, HP:0003196, HP:0000414, HP:0000463, HP:0000288, HP:0000160, HP:0000219, HP:0000232, HP:0000307, HP:0000400, HP:0200055, HP:0001769, HP:0006045, HP:0004209, HP:0010610, HP:0001795, HP:0000193, HP:0003100, HP:0000938, HP:0002750, HP:0002205, HP:0000565, HP:0011968

CasePResentingHPOText: Subject began walking at 5 y.o. First words at 8 y.o. and noted as only having 2 words. Seizure onset at 3 y.o. with general tonic clonic seizures and absence. At 4 y.o. noted as having little social interaction, and intermittent hand flapping. Noted as having a feeding tube until age 8.

CaseNOTHPOs: HP:0002376, HP:0012443, HP:0002360

CasePreviousTesting: Affymetrix Cytogenetics 2.7 array testing was unremarkable.

CaseGenotypingMethod: Trio-WES. Testing also identified a de novo VUS in SMARCAD1 (NM_0011 28429.1):c hr4:g.9520 1881T>A, c.2563T>A, p.(Ser855Thr), this gene is associated with skin disease.

Variant: hg19:chr2: g.4804614 7G>C, c.1868C>G , p.(Thr623Arg) OR NM_001190274.1:c.1868C>G

CA ID: CA346764020

de novo Trio-WES performed so maternity and paternity could be investigated with this method.

gnomAD: n/a

AddCaseInfo:

VariantEvidence: Thr623 is located in the second CASH domain of FBXO11, and is conserved across specieis. These domains are responsible for the substrate recognition. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the T623R mutation on FBXO11 function.

Case#: N6287, M, 59 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0100543, HP:0002483

CaseNotHPOs:

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c1312G>A p.Asp438Asn

CAID: CA65993021

gnomAD: 2-220115109-C-T; Total overall AF (non-neuro) = 0.000009617; gnomAD_NM_006000.3(TUBA4A):c1312G>A p.Asp438Asn

CaseAddInfo: dbSNP ID: rs913033084. While most cases were found to be negative during pre-screening for known mutations, some cases were positive for mutations in SOD1 (n=4), C9orf72 (n=12), TARDBP (n=4), & FUS/TLS (n=1) genes. Whether this case tested positive for any of these is not specified.

Case: Family E/Hussain Patient 1, female, Pakistan, 9mo at onset

CasePresentingHPOs: HP:0000508, HP:0000369, HP:0000316, HP:0001993, HP:0001738, HP:0002720, HP:0000953, HP:0000998, HP:0001433, HP:0002594, HP:0006610, HP:0100578, HP:0001508, HP:0001945, HP:0002254, HP:0002716, HP:0001903, HP:0001541, HP:0012398, HP:0000103, HP:0001959, HP:0100651, HP:0004322, HP:0001007, HP:0100679, HP:0003565, HP:0011227, HP:0002094, HP:0001254, HP:4000141, HP:0000545, HP:0000483, HP:0012716, HP:0025289, HP:0034752, HP:0034751, HP:0000581, HP:0003237

CasePresentingHPOsFreeText: Inflammatory symptoms. Hyperpigmentation onset at 9mo; located on limbs and back. Lipoatrophy of buttocks. Biopsies from both lymph nodes and subcutaneous tissue showed fibrofatty connective tissue with fibrosis and mononuclear cell infiltrates around the larger vessels.

CaseNOTHPOs: HP:0000520, HP:0006476, HP:0025329, HP:0001263, HP:0000488, HP:0009830

CaseNOTHPOSFreeText:

CasePreviousTesting: ADAMTS14, C10orf27, CDH23, EIF4EBP2, LRRC2, KIAA1274, NODAL, NPFFR1, PCBD1, PPA1, PRF1, SLC29A3, SGPL1, UNC5B were sequenced since they were positional candidate genes

CaseGenotypingMethod: homozygosity mapping (10K SNP array), candidate gene sequencing

Variant: c.1346C>G (p.Thr449Arg)

ClinVarID: or CAID: CA114354

gnomAD: This missense variant, p.Thr449Arg is present in gnomAD v4.0.0 with a MAF=0.00006956 (6/86258 alleles) in the South Asian population and 0 homozygotes. Downscoring for homozygosity since the parents are consanguineous.

AddCaseInfo: first cousin parents. sister is genotype and phenotype +

PreviouslyPublished: 19175903

VariantEvidence: Functional studies in Xenopus oocytes showed transport activity that was approximately one-fourth lower that of WT SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated slightly increased turnover of the T449R mutant compared to WT, suggesting decreased stability (Kang et al. 2010; PMID: 20595384).

This variant is mentioned as a reference to a previous publication (PMID: 20157015) which has already been included in the VCI.

Case#: Family NO-1, 60yo, male, Norwegian

DiseaseAssertion: DOA+

FamilyInfo: positive family history: affected sister with same genotype, 2 unaffected daughters with only the c.768C>G p.S256R variant. Parents are deceased but were apparently healthy

CasePresentingHPOs: HP:0000648, HP:0001251, HP:0003198, HP:0009830, HP:0001257

CaseHPOFreeText: corticospinal tract involvement

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing. Initial screens for POLG1, POLG2, PEO1 and SLC25A4 were found to be negative,

Variant: c.768C > G (p.S256R) and c.854A > G (p.Q285R), confirmed in trans by haplotype analysis

CAID: CA355787228

SupplementalData: n/a

Case#: Family FR-1, 30yo, male, French

DiseaseAssertion: DOA+

FamilyInfo: positive family history, but no information provided

CasePresentingHPOs: HP:0000648, HP:0000365, HP:0001251, HP:0003198, HP:0001138

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing

Variant: c.1635C>G (p.S545R) aka c.1800C>G (p.S600R)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

Case: de Pontual Family VII Patient 7, male, 14yo at dx, 5yo at onset, Moroccan

CasePresentingHPOs: HP:0100651, HP:0001738, HP:0031685, HP:0002570, HP:0001742, HP:0003565, HP:0010702, HP:0030044, HP:0030839, HP:0002833

CasePresentingHPOsFreeText: Levels of fat in stool at 12 g/24 hr. Infiltrates found in both the nose and the right maxillary sinus. initial diagnosis of rhinoscleroma. High erythrocyte sedimentation rate (>50 mm). Polyclonal hypergammaglobulinemia (IgG = 15.3 g/l, IgA = 4.2 g/l, IgM = 2.8 g/l). Lytic bone lesions of both patellas on X-ray. Diabetic retinopathy. Mucosa displayed fibrosis and a mild to moderate inflammatory infiltrate containing plasma cells, lymphocytes and some vacuolated histiocytes. Parts of the biopsy specimens also displayed specific features of Rosai-Dorfman histiocytosis, as they contained several large histiocytes with emperipolesis. These histiocytes were positive for CD68, CD4 and S100 protein. Mononucleated vacuolated and spumous macrophages.

CaseNOTHPOs: HP:0012090, HP:0001627, HP:0000998, HP:0000554, HP:0000953, HP:0000407, HP:0002240, HP:0004322, HP:0000135, HP:0000771, HP:0000823, HP:0001822, HP:0011974, HP:0005200, HP:0002716

CaseNOTHPOSFreeText: Cystic fibrosis. Histiocytic infiltration. Wartin-Starry, Grocott and periodic acid-Schiff (PAS) stains

CasePreviousTesting:

CaseGenotypingMethod: genome-wide linkage (GWL) analysis by homozygosity mapping and whole-exome sequencing (WES) by next-generation deep sequencing. Sanger sequencing for validation.

Variant: c.243delA (p.Lys81fs) homozygous

ClinVarID: or CAID: 636986 / CA913184824

gnomAD: This frameshift variant, Lys81fs which is occurs in exon 2, is absent from gnomAD. Down-scoring for consanguinity and alternative splicing.

AddCaseInfo: First-cousin, heterozygous parents. Proband has 1 affected sister who is also a homozygote. Proband also has a variant in VCL (c.610G>C) which is predicted benign and associated with HCM, which the proband does not have.

PreviouslyPublished: PMID: 18947330

VariantEvidence: This mutation decreases the levels of transcript variant 1 through NMD and results in an absence of the WT protein, but allows the expression of a mutated mRNA transcript variant 3, which would ordinarily be subject to NMD. This hENT3-variant3-81fs variant was expressed but displayed lower levels of adenosine transporter activity than the hENT3-variant1-WT protein.

Case# Subject 2, F, 6mo onset, Hispanic/European

CasePresentingHPOs HP:0001942, HP:0003128, HP:0002919, HP:0001987, HP:0002094, HP:0006682, HP:0004756, HP:0045045, HP:0001288, HP:0002013, HP:0007340, HP:0002913, HP:0002058, HP:0002307, HP:0001260, HP:0001251, HP:0003201, HP:0002151, HP:0001249, HP:0001943, HP:0003236, HP:0005184, HP:0002910, HP:0012544, HP:0006956, HP:0100960, HP:0001254

HPOcont: Metabolic acidosis, Lactic acidosis, Ketonuria, Hyperammonemia, Dyspnea, Ventricular extrasystoles, Ventricular tachycardia, Elevated acylcarnitine, Gait abnormality, Emesis, Lower limb muscle weakness, Myoglobinuria, Myopathic facies, Drooling, Dysarthria, Ataxia, Rhabdomyolysis, Elevated Lactate, Intellectual Disability, Hypoglycemia, Elevated CPK, Prolonged QTc interval, Elevated Transaminases, Elevated aldolase, Lateral ventrical dilation, Asymmetric ventricles, Lethargy

HPOFreeText: (6 months) metabolic acidosis, lactic acidemia, ketonuria, elevated blood ammonia and Kussmaul breathing, in addition to prolonged QTc interval, premature ventricular contractions just short of ventricular tachycardia, and elevated acycarnitine profile. (16 months) gait abnormality, weakness, sore troat, and vomiting. (5 years) after infection, lethargy, lower limb weakness, myoglobinuria, elevated CPK, transaminases, lactate, and aldolase in additon to myopathic face, drooling, dysarthric speech and ataxia.

CaseNotHPOs HP:0001250

NotHPOcont: Seizures

CasePreviousTesting "metabolic acidosis (pH of 7.0; base deficit of 20 mEq/l) and lactic acidemia of 15 mmol/l (normal range 0.2–2.0 mmol/l), serum ammonia was mildly elevated to 138 μmol/l. Acylcarnitine profile showed a primary peak of C14:1 in addition to C14:2, C16, C18, and some hydroxy derivatives." At 15 months of age "CPK of 1,126 U/l, AST of 158 U/L, mildly elevated ammonia of 71 μmol/l, and lactate of 7.0 mmol/l, then at 5 years, CPK of 287,230 U/l, hypoglycemia (glucose of 17 mg/dl), elevated transaminases (AST of 7,618 U/l and ALT of 2,564 U/l), lactate was 2.0 mmol/l, aldolase level was 595 U/l (normal range 2.7–8.8 U/l). Renal function tests remained stable throughout admission. Etiologic evaluations, including DNA sequencing of ACADVL for VLCAD deficiency, muscle histopathology, quantitative mtDNA studies in muscle, and mitochondrial genome sequencing for common point mutations and deletions, were normal."

CaseMethod1 WES

CaseMethod2 PCR

CaseGenotypingMethod WES and cSNP array, validated deletion variant with PCR

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg), (2) ~34kb, exon3-9del

ClinVar (1) 208823

CAID (1) CA358646

gnomAD (1) 0.001549(Other), 0.0001208(Overall)

VariantEvidence (1)(Figure 3) using "EBV-transformed B-lymphoblastoid cell lines (BLCLs) from another individual, subject 4 with homozygous c.460G>A (p.Gly154Arg) mutation, and evaluated the Golgi by intracellular staining with WGA, as well as cis Golgi marker, anti-GM130 antibody." WGA stain resolved lower area of golgi bodies in p.Gly154Arg cells than WT. Measured immunoglobulin heavy chain binding protein levels in WT and and patient fibroblasts, BiP levels in patient cells lower than WT after ER induced stress by Brefeldin A.

CaseAddInfo nonconsanguineous, found deletion variant in with PCR father and mother carried missense

CasePMIDs n/a

Case# Subject 6, M, 1yo onset, Hispanic

CasePresentingHPOs HP:0001263, HP:0002098, HP:0002013, HP:0001943, HP:0001942, HP:0002151, HP:0001290, HP:0001987, HP:0001249, HP:0001946, HP:0045045, HP:0040145, HP:0001508, HP:0003648

HPOcont: Global developmental delay, Respiratory Distress, Emesis, Hypoglycemia, Metabolic acidosis, Elevated Lactate, Generalized hypotonia, Hyperammonemia, Intellectual Disability, Ketosis, Elevated acylcarnitine, Dicarboxylic acidemia, Failure to thrive, Lacticaciduria

HPOFreeText: (1 year) developmental delay, emesis, difficulty breathing, elevate metabolites, elevated urine organic acids, elevations of 3-hydroxy-N-butyric and acetoacetic acids (ketone bodies), as well as adipic, suberic, sebacic, and 3-hydroxysebacic (dicarboxylic) acids. Found to also have a head circumference in 6th percentile and hypotonia.

CaseNotHPOs HP:0001250, HP:0011675, HP:0003201

NotHPOcont: Seizures, Arrhythmia, Rhabdomyolysis

CasePreviousTesting Tested blood gas pH (7.1), serum bicarbonate(16 mEq/L (normal range 22-28 mEq/L)), serum lactate(11.7 mmol/L), serum ammonia( 102 μmol/L), elevated very long chain acylcarnitine species, especially C14, normal serum CPK. Chromosomal microarray and Fragile X results were normal.

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod WES and cSNP array

Variant NM_152906.6(TANGO2):c.605+1G>C

ClinVar 521699

CAID CA358646

VariantEvidence splice site

CaseAddInfo consanguineous parents

CasePMIDs n/a

Patient: 5 unrelated patients

Variants: c.550G>C; c.550G>A; c.550+5G>A

CAIDs: CA380695714; CA219267; CA599664126

FunctionalEffect: RT-PCR of mRNA samples from patients blood showed an additional transcript lacking exon 3. Expression in agarose gels revealed a higher expression of the exon 3 skipped variant in these pts vs controls.

CA2860239Allele Registry

PMID: 9660054

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Family#PresentingHPOs: HP:0000884, HP:0005619, HP:0002761, HP:0012069

CountryOrigin: Poland

Family#Method1: SSCP

Family#Method2: Sanger

Family#GenotypingMethod: SSCP followed by sanger sequencing of mobility variants

Affected: 3

Unaffected: 2

Segregations: 3

eLOD: 1.45

AddSegregationInfo: II:2 and II:7 were not genotyped and not counted, III:1 and III:2 had a greater than 0.25 chance since mother was homozygous so they can not be counted

ProbandLabel: TM

Variant: R259Q and R94G

ClinVar: 706 & 705

CAID: CA251569 & CA251568

gnomAD: 16-88901743-C-T & n/a

Case# Arno P3, German, Male

CasePresentingHPOs HP:0000545, HP:0025313, HP:0007994

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod Sanger of RBP3 exons

Variant NM_002900.2:c.1530T>A

CAID CA376670175

CaseAddInfo in trans

Case# Patient2, F, 5yo report, Chinese

CasePresentingHPOs HP:0000325, HP:0002007, HP:0000347, HP:0008897, HP:0001508, HP:0001249, HP:0000750, HP:0001270, HP:0008947, HP:0002360

HPOcont: Triangular face, Frontal bossing, Micrognathia, Postnatal growth retardation, Failure to thrive, Intellectual disability, Delayed speech and language development, Motor delay, Infantile muscular hypotonia, Sleep disturbance

Free Text: "The patient was referred for DD and failure to thrive without feeding difficulty at approximately three years of age. She could speak only simple words such as “baba” and “mama” and could not walk. A physical examination revealed hypotonia. Her head circumference was 44 cm (−3.7 SD). Her facial dysmorphisms included a triangular face; light, sparse hair; frontal bossing; strabismus; a thin upper lip; and micrognathia. At the age of five, she could stand with support but remained unable to ambulate or speak. She suffered from sleep disturbance and a tendency toward self-injury behaviors, such as hitting her head with her hands or bumping her head. Follow-up when the patient was 5 years and 9 months old showed that she could not walk or speak. At that time, her body length was 100 cm (−3.4 SD), and she weighed 11 kg (−4 SD)."

CaseNotHPOs HP:0000494, HP:0000369, HP:0002353, HP:0000358, HP:0000431, HP:0000319, HP:0012299, HP:0001182, HP:0001511, HP:0001250, HP:0002650, HP:0011968, HP:0002019

NotHPOcont: Downslanted palpebral fissures, Low-set ears, EEG abnormality, Posteriorly rotated ears, Wide nasal bridge, Smooth philtrum, Long distal phalanx of finger, Tapered finger, Intrauterine growth retardation, Seizures, Scoliosis, Feeding difficulties, Constipation

CasePreviousTesting Echocardiographic examination, brain magnetic resonance imaging (MRI) and an EEG revealed no abnormalities. Metabolic screening and assessments of the patient's thyroid function at age three produced normal results.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES, confirmed with Sanger

Variant (1) NM_032504.1:c.3719G>A (p.Trp1240Ter ), (2) NM_032504.1:c.4926_4937del (p.Asn1643_Leu1646del)

CAID (1) CA350741683 (2) CA658820715

CaseAddInfo nonconsanguineous parents, no parent testing mentioned, "younger brother presented similar phenotypes such as hypotonia and developmental delay. He died at the age of one year due to severe pneumonia. He was diagnosed as IHPRF2 clinically. However, no genetic analysis was performed, as DNA was unavailable."

Case# Patient1, Male, 1 week onset, Chinese

CasePresentingHPOs HP:0002007, HP:0000319, HP:0012299, HP:0001249, HP:0000750, HP:0001270, HP:0008947, HP:0001250, HP:0002019, HP:0002353, HP:0010804, HP:0000486

HPOcont: Frontal bossing, Smooth philtrum, Long distal phalanx of finger, Intellectual disability, Delayed speech and language development, Motor delay, Infantile muscular hypotonia, Seizures, Constipation, EEG abnormality, Tented upper lip vermilion, Strabismus

Free Text: "He experienced physiologic jaundice one week after birth. Hypotonia and psychomotor retardation were observed. He could raise his head at the age of one year and sit by himself when he was two years of age; he ambulated when he was three years old. At approximately five years of age, he could use only simple speech. He also exhibited poor balance and displayed hyperactive behavior and a happy and excitable disposition with frequent smiling and laughing. In addition, he suffered from constipation. Seizures occurred when he was two years old and were effectively treated with valproate and levetiracetam. When he was referred to our clinic at 6 years and 5 months of age, his height and weight were 120 cm (0 SD) and 20 kg (0 SD), respectively. When followed up at the age of 9.5 years, his height, weight and head circumference were 135 cm (−0.5 SD), 25 kg (−1.3 SD) and 51 cm (−0.5 SD), respectively. His facial features included frontal bossing, strabismus, a tented upper lip, a broad nasal bridge, and a short, smooth philtrum. He had long, slender fingers. An electroencephalograph (EEG) revealed excessively slow background."

CaseNotHPOs HP:0000494, HP:0000325, HP:0000369, HP:0000358, HP:0000431, HP:0000347, HP:0001182, HP:0001511, HP:0008897, HP:0001508, HP:0002650, HP:0011968, HP:0002360

NotHPOcont: Downslanted palpebral fissures, Triangular face, Low-set ears, Posteriorly rotated ears, Wide nasal bridge, Micrognathia, Tapered finger, Intrauterine growth retardation, Postnatal growth retardation, Failure to thrive, Scoliosis, Feeding difficulties, Sleep disturbance ,

CasePreviousTesting "methylation-specific multiplex ligation-dependent probe amplification revealed no abnormalities in the 15q11-q13 region. Chromosomal microarray tests also showed no pathogenic copy number variations."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES, confirmed with Sanger

Variant (1) NM_032504.1(UNC80):c.4963C>T (p.Arg1655Cys), (2) NM_032504.1:c.8385C>G (p.Tyr2795Ter)

ClinVar (1) 545035

CAID (2) CA350413549

CaseAddInfo nonconsanguineous, parent testing not mentioned

From supplemental tables S2 and S3 (authors used hg19 alignment).

MONDO: MONDO:0005144 for FALS

Case#7: Smith 2014 FALS K430N, F, 64 y.o. onset, Italy

CasePresentingHPOs: HP:0007354

CaseHPOFreeText: spinal-onset ALS with upper and lower motor neuron signs

CasePreviousTesting: All FALS were screened for known causative mutations/repeat expansions in SOD1, C9orf72, TARDBP, FUS, PFN1, UBQLN2, OPTN, VCP and ANG and removed from cohort if positive for variant.

CaseMethod1: This case identified through case-control study

CaseGenotypingMethod: Exome sequencing, confirmed with Sanger sequencing.

Variant: NM_006000.3(TUBA4A):c.1290G>C (p.Lys430Asn)

CAID: CA350721313

CaseAddInfo: This variant found in 0/13023 control samples. This variant did not co-segregate with an affected cousin of the sequenced proband.

Case#: Coletti Patient 23, US

DiseaseAssertion: MPS1, Hurler

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: "diagnosis was confirmed by clinical phenotype and low IDUA activity in peripheral blood leukocytes." umbilical cord blood transplantation

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: sequencing of the IDUA gene was performed, and mutations were confirmed by restriction fragment length analysis or allele-specific oligonucleotide analysis

PreviouslyPublished: n/a

Variant: W402X; R628X

ClinVar: 550421

CAID: CA2802462

gnomAD: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00005038 (2/39700 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).

SupplementalData: n/a

Case#: Hein Proband, Australian

DiseaseAssertion: MPS I, attenuated

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: IDUA activity=0.43±0.06 pmol/min per mg

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod:

PreviouslyPublished: n/a

Variant: R628X/W402X

ClinVar: 11908; 550421

CAID: CA220498; CA2802462

SupplementalData: n/s