CaseGSHSP44: Female, 44 yrs onset, Australia/UK

CasePresentingHPOs: HP:0040083, HP:0002317, HP:0002064, HP:0002460, HP:0002395, HP:0007350, HP:0003487, HP:0000012, HP:0012104, HP:0006913, HP:0001761, HP:0031520, HP:0006827 (Toe walking, Unsteady gait, Spastic gait, Distal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary urgency, Parietal cortical atrophy, Frontal cortical atrophy, Pes cavus, Groin pain, Atrophy of the spinal cord)

HPOsFreeText: 4/7 disability score, Hip replacement

CaseNotHPOs: HP:0001317, HP:0002464, HP:0100543, HP:0000973, HP:0006938 (Abnormal cerebellum morphology, Spastic dysarthria, Cognitive impairment, Cutis laxa, Impaired vibration sensation at ankles)

NotHPOsFreeText: N/A

CaseGenotypingMethod: Exome sequencing data of 160 index patients with autosomal dominant spastic paraplegia and 275 index patients with autosomal recessive or sporadic spastic paraplegia was examined. 95 patients were screened through panel sequencing. Any determined ALDH18A1 mutations were confirmed by Sanger sequencing.

CasePreviousTesting: N/A

CaseAddInfo: Case is sporadic

Variant reported as c.1949G>T which does not exist in current transcripts

Variant: NM_002860.3:c.1955C>T (p.Ser652Phe)

CAID: CA377700120 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA377700120

gnomAD: Not in gnomAD

Case41: 6 mo (at biopsy), Pakistani

Case 41 (Level 2)

CasePreviousTesting: same as group. found 0.6 nmol/mg protein/18 h propionate incorporation, 0.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1560G>C (p.Lys520Asn)

ClinVar: n/a

CAID: CA364397073

gnomAD: n/a

CaseAddInfo: mut0 type, homozygous mutations.

Case40: Middle Eastern

Case 40 (Level 2)

CasePreviousTesting: same as group. found 1.8 nmol/mg protein/18 h propionate incorporation, 1.6 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1420C>T (p.Arg474Ter)

ClinVar: 554873

CAID: CA138795916

gnomAD: 0.00003267 (South Asian)

CaseAddInfo: mut0 type, homozygous mutations. documented consanguinity.

Case39: 1 y (at biopsy), Asian

Case 39 (Level 2)

CasePreviousTesting: same as group. found 1.4 nmol/mg protein/18 h propionate incorporation, 1.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1280G>A (p.Gly427Asp)

ClinVar: 218990

CAID: CA347873

gnomAD: 0.0004011 (East Asian)

CaseAddInfo: mut0 type, homozygous mutations. documented non-consanguinity.

Case38: 9 y (at biopsy), German/Polish

Case 38 (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: mut0 type, homozygous mutations.

Case37: 18 mo (at biopsy), Moroccan

Case 37 (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.5 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.683G>A (p.Arg228Gln)

ClinVar: n/a

CAID: CA3847070

gnomAD: 0.00002905 (Latino)

CaseAddInfo: mut0 type, homozygous mutations.

Case36: 14 mo (at biopsy), Hispanic

Case 36 (Level 2)

CasePreviousTesting: same as group. found 0.7 nmol/mg protein/18 h propionate incorporation, 0.8 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.406G>T (p.Val136Phe)

ClinVar: n/a

CAID: CA364404792

gnomAD: n/a

CaseAddInfo: mut0 type, homozygous mutations. documented consanguinity.

Case35: 5 y (at biopsy), Hispanic

Case 35 (Level 2)

CasePreviousTesting: same as group. found 0.5 nmol/mg protein/18 h propionate incorporation, 0.7 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

CaseAddInfo: mut0 type, homozygous mutations.

Case33: 9 mo (at biopsy), Hispanic

Case 33 (Level 2)

CasePreviousTesting: same as group. found 1.0 nmol/mg protein/18 h propionate incorporation, 1.3 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

CaseAddInfo: mut0 type, homozygous mutations.

Case32: 10 y (at biopsy), Arab

Case 32 (Level 2)

CasePreviousTesting: same as group. found 1.0 nmol/mg protein/18 h propionate incorporation, 1.0 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.278G>A (p.Arg93His)

ClinVar: 1880

CAID: CA249728

gnomAD: 0.0004777 (European- Finnish)

CaseAddInfo: mut0 type, homozygous mutations. documented consanguinity.

Case34: 3.5 wks (at biopsy), White/Hispanic

Case 34 (Level 2)

CasePreviousTesting: same as group. found 1.6 nmol/mg protein/18 h propionate incorporation, 1.8 nmol/mg/protein/18 h propionate incorporation with hydroxocobalamin supplementation

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.322C>T (p.Arg108Cys)

ClinVar: 1887

CAID: CA249732

gnomAD: 0.0008393 (Latino)

CaseAddInfo: mut0 type, homozygous mutations.

Case3: Female, 5 yrs report

CasePresentingHPOs: HP:0012072 (Aciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo:

CasePreviousTesting: Partial biotinidase deficiency (19%) was confirmed; Urine AAA (552 mmol/mol creatinine; ref <91) and KAA (251 mmol/mol creatinine) were clearly increased. At 5 years of age, urine AAA and KAA as well as plasma AAA were persistently elevated.

CaseGenotypingMethod: All 17 exons and flanking intronic sequences of DHTKD1 were Sanger sequenced.

Variant1: NM_018706.5(DHTKD1):c.2185G>A (p.Gly729Arg)

ClinVar: 39564 https://www.ncbi.nlm.nih.gov/clinvar/variation/39564/

gnomAD: 0.002748, https://gnomad.broadinstitute.org/variant/10-12154929-G-A

Variant2: NM_018706.7(DHTKD1):c.1309G>T (p.Glu437Ter)

ClinVar: 574714 https://www.ncbi.nlm.nih.gov/clinvar/variation/574714/

gnomAD: 0.0001316, https://gnomad.broadinstitute.org/variant/10-12136221-G-T

CaseF6P: 1 yr 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, Predicted to undergo NMD

CasePreviousTesting: Blood phenylalanine before treatment was 1260 μmol/l, Blood tyrosine before treatment was N/A 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(PAH):c.526C>T (p.Arg176Ter)

ClinVar: 102723 https://www.ncbi.nlm.nih.gov/clinvar/variation/102723/

gnomAD: 0.00008012, http://gnomad.broadinstitute.org/variant/12-103249094-G-A

Case1: Male, Chinese, 11 mo (at end of study)

Case1HPOs: HP:0012736 (profound psychomotor retardation)

HPOsFreeText: 10 mo at onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case1 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

CaseAddInfo: homozygous mutations

Case4: Male, Chinese, 2.8 y (end of study)

HPOsFreeText: poor neurologic outcome, neonatal onset

NotHPOsFreeText: not responsive to vitamin B12

Case4 (Level 2):

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

CaseAddInfo: homozygous mutations

Case5: Female, Chinese, 1.6 y (onset)

HPOsFreeText: 1.6 y onset

NotHPOsFreeText: Not responsive to vitamin B12

Case5 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000255.3:c.1106G>A (p.Arg369His)

ClinVar: 203846

CAID: CA312764

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: homozygous mutations, lost to follow up

Case3: Female, Chinese, 4 mo (end of study)

HPOsFreeText: Responsive to vitamin B12

Case3 (Level 2):

CasePreviousTesting: NBS

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000255.3:c.599T>C (p.Ille200Thr)

ClinVar: n/a

CAID: CA364404381

gnomAD: n/a

CaseAddInfo: homozygous mutations, asymptomatic

Case2: Male, Chinese, 3 mo (age at death)

HPOsFreeText: Neonatal onset

NotHPOsFreeText: Not responsive to vitamin B12

Case2 (Level 2):

CasePreviousTesting: NBS (newborn screening)

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000255.3:c.482G>T (p.Gly161Val)

ClinVar: n/a

CAID: CA364404636

gnomAD: n/a

CaseAddInfo: homozygous mutations, novel mutation

CaseAL1: Male, 14 yrs report

CasePresentingHPOs: HP:0012120 (Methylmalonic aciduria)

HPOsFreeText: Malonic acidemia/uria

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Born to non-consanguineous Ashkenazi Jewish parents; Proband is confirmed homozygous via parental testing

CasePreviousTesting: Newborn screening identified these probands, with subsequent urine organic acid analysis by gas chromatography mass spectroscopy confirming CMAMMA; Initial urine MMA level was 891 μmol/mmol creatinine; Confirmatory testing showed a urine MMA of 745 μmol/mmol creatinine (normal <25) and MA of 60 μmol/mmol creatinine (normal <6); Plasma MMA level was 18 μmol/l (normal <0.5); No other organic acid abnormality was detected. Carnitine levels, acylcarnitine profiles, plasma amino acids, ammonia, blood gas values, total homocysteine, folate and vitamin B12 levels were all within reference ranges, and the mothers were not vitamin B12 deficient; MCD activity in fibroblasts were within the reference range

CaseGenotypingMethod: Genomic DNA was isolated from fibroblasts and all exons and flanking introns of MLYCD, along with ACSF3, were subject to Sanger sequencing.

Variant: NM_001243279.3:c.1411C>T (p.Arg471Trp)

ClinVar: 31137, https://www.ncbi.nlm.nih.gov/clinvar/variation/31137

gnomAD: 0.007046, https://gnomad.broadinstitute.org/variant/16-89211719-C-T

Case14 29yo diagnosis, Australia, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0002751, HP:0000939

(Lens dislocation, Kyphoscoliosis, Osteoporosis)

HPOsFreeText Diagnosis was based on dislocated lens and skeletal deformity. Patient has severe kyphoscoliosis. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient had a partial response to the treatment. Homocystine levels were sharply reduced on pyridoxine and folate treatment, but levels did not fall below 20μmol (nv <60μmol) on this treatment alone. (PMID:9156316:): In this study, patient was found to have mild intellectual disability and osteoporosis at 50yo.

CaseNotHPOs HP:0001249

(Intellectual disability)

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. (PMID:9156316): Serum homocysteine was 100μmol/l and methionine was 18μmol/l after five years of treatment. Addition of betaine(3g twice per day) lowered homocysteine to 18μmol/l which remained <50μmol for years.

CaseMethod1 PCR

CaseMethod2 Sanger

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

Variant 1. NM_000071.2(CBS):c.833T>C (p.Ile278Thr), 2. NM_000071.2(CBS):c.1058C>T (p.Thr353Met), comp het

ClinVar 1. 120, 2. 131

gnomAD 1. MAF=0.001432(European(non-Finnish)), no homozygotes, 2. MAF=0.0002916(African), no homozygotes

CaseAddInfo Patient carries a common 68bp insertion, 88ins68, variant that does not cause hyperhomocysteinemia. (PMID:9156316): Additionally is heterozygous for a c.699C>T(Y233Y) synonymous variant as well as homozygous c.1080T>C(A360A) synonymous variants.

CasePMIDs 9156316

Case24 6yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Patient had marfanoid features and was diagnosed on the basis of dislocated lenses. 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 HP:0001249

(Intellectual disability)

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(CBS):c.904G>A (p.Glu302Lys), 2. NM_000071.2(CBS):c.430G>A (p.Glu144Lys); 3. NM_000071.2(CBS):c.1316G>A (p.Arg439Gln), comp het, 2&3 in cis

ClinVar 1. 496864, 2. 122; 3. 189088

gnomAD 1. MAF=0.00006153(African), no homozygotes 2. MAF=0.00009799(South Asian), no homozygotes, 3. MAF=0.00005341(African), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

CaseBII-2: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 270 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.688G>A (p.Val230Ile)

ClinVar: 102784 https://www.ncbi.nlm.nih.gov/clinvar/variation/102784/

gnomAD: 0.0009025, https://gnomad.broadinstitute.org/variant/12-102855154-C-T?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.1241A>G (p.Tyr414Cys)

ClinVar: 593 https://www.ncbi.nlm.nih.gov/clinvar/variation/593/

gnomAD: 0.0005264, https://gnomad.broadinstitute.org/variant/12-102840474-T-C?dataset=gnomad_r3

Case#: Patient 14, N/A (onset), China

CasePresentingHPOs:

HPOsFreeText: Classic form of MSUD.

CasePreviousTesting: Diagnosed based on elevated blood levels of leucine, valine and the ratio of leucine to phenylalanine (tandem mass spec), as well as abnormal urine BCKAs (gas phase chromatography-mass spec). . CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA from peripheral blood leukocytes from patients and parents extracted. PCR amplification of exons and intron/exon boundaries for BCKDHA, BCKDHB, DBT.

Variant: 1. NM_001918.3(DBT):c.713delC (homozygous)

CAID: CA658820836

gnomAD: Not in gnomAD

VariantEvidence: Predicted LOF

CaseAddInfo: Parents tested.

Case#: Patient 14, 1 month (onset), China

CasePresentingHPOs: HP:0001328, HP:0008344

HPOsFreeText: Classic form of MSUD.

CasePreviousTesting: Diagnosed based on elevated blood levels of leucine, valine and the ratio of leucine to phenylalanine (tandem mass spec), as well as abnormal urine BCKAs (gas phase chromatography-mass spec). . CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA from peripheral blood leukocytes from patients and parents extracted. PCR amplification of exons and intron/exon boundaries for BCKDHA, BCKDHB, DBT.

Variant: 1. NM_001918.3(DBT):c.372_377del (homozygous)

CAID: CA658820835

gnomAD: Not in gnomAD

VariantEvidence: In frame deletion

CaseAddInfo: Parents tested.

Case#: Case report, 8 year old (report), male

CaseHPOs: See free text

CaseHPOsFreeText: In the newborn period – hypotonia, torticollis, right inguinal hernia (surgically repaired). Concern about delays at 4 months of age. First evaluated at 19 months. No NAA or NAAG signal on neurospectroscopy (at 2 years 3 months, and 3 years 6 months). At 8 years, “profound neurological dysfunction”, can walk unaided for short distances, ataxic gait, no speech but can make sounds, behavior abnormalities, microcephaly, profound intellectual impairment (<12 month level), generalized seizures beginning at 5 year 9 months of age with 9 episodes of status epilepticus, tendency to self mutilation if left alone, drools.

CaseNotHPOs: No dysmorphic features. Normal vision and hearing. Normal brain anatomy on MRI.

CasePreviousTesting: MR spectra of urine, plasma, and CSF were unremarkable (3 years 10 months, 5 years 6 months). The latter samples were analyzed by capillary electrophoresis (CE) and revealed no detectable NAA in CSF (this is also seen in controls, and therefore normal). No detectable NAAG (usually in the uM range in controls). CE of urine – NAA 21.0 umol/mmol creatinine and NAAG 1.9 umol/mmol creatinine (within the normal range). Normal plasma amino acids, urine organic acids, oligosaccharides, mucopolysaccharides. No evidence for mitochondrial, organic acid, amino acid, or peroxisomal disorder. CSF normal for cell count, glucose, protein, biogenic amines, folates, and pterins (on two occasions).

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: The three exons of NAT8L were amplified and sequenced.

Variant: NM_178557.4(NAT8L):c.212_230del (p.Gly71fs)

ClinVar: 30849

gnomAD: Not in gnomAD

VariantEvidence: Expression of cDNA containing the variant in HEK-293 cells resulted in no enzyme activity and no cross-reactive material.

CaseAddInfo: “Born in an Eastern European country”, adopted by a family is Switzerland. Exposure to cigarettes and alcohol during the pregnancy.

CasePMIDs: 15328569, 16802720

Case#: 3 years (report), male, Pakistan

CasePresentingHPOs: HP:0008947, HP:0001270, HP:0003700, HP:0000486, HP:0008315, HP:0011936

HPOFreeText: Became increasingly floppy in 2nd year of life, able to walk with support at 3 years, normal MRI (2 years), urinary organic acid consistently showed 2-methylbutyrylblycinuria with excretion of trace amounts of isobutyrylglycine. NBS blood spot showed normal acylcarnitine profile.

CasePreviousTesting: Total RNA extracted from fibroblasts, cDNA synthesized, PCR amplification of entire coding region of SBCAD cDNA and ACAD-8 cDNA, bidirectional sequencing. Enzyme activity of ACAD toward 2-methylbutyryl-CoA in fibroblasts was 10% of controls (0.016 nmol/min/mg protein vs 0.157 nmol/min/mg protein).

CaseGenotypingMethod: PCR and sequencing of ACADSB cDNA, followed by genomic DNA.

Variant: NM_001609.3(ACADSB):c.1228G>A (p.Gly410Ser)

ClinVar: 9199

gnomAD: 0.00002949 overall (no homozygotes)

VariantEvidence: The 1228G>A variant is in the last nucleotide in the skippped exon 10. cDNA analysis from the patient showed no normal-sized ACADSB mRNA. Northern blot of total RNA from fibroblasts showed normal levels of mRNA.

CaseAddInfo: Patient also heterozygous for the SCAD A625 polymoprhism (Corydon, 1996). Healthy father and siblings were heterozygous for the deletion, while mother was also homozygous and found to excrete 2-methylbutyrylglycine in her urine.

CaseG1 Female, 17mo report, Turkish

CasePresentingHPOs HP:0003270, HP:0002013, HP:0000737, HP:0011169, HP:0010818, HP:0001336, HP:0011182

(Abdominal distension, Vomiting, Irritability, Clonic seizures, Generalized tonic seizures, Myoclonic jerks, Epileptiform EEG discharges)

HPOsFreeText born at 40wks gestation. (neonatal, pre-treatment:) abdominal distension, vomiting, irritability, 3wks onset of clonic and generalized tonic fits as well as myoclonic jerks, epileptiform discharges with normal background activity, resistance to ACD's. Pyridoxine trial introduced at 9wks, trial dose/route of 10mg/kg/d p.o., complete cessation of seizures, but experienced hypotonia/sleepiness, no apnoea or hypotension, initial maintenance daily dose=10mg/kg. Withdrew form trial at 7mo, seizures recurred after 17 days.

CaseNotHPOs HP:0001557, HP:0025116, HP:0001941, HP:0002098, HP:0001290, HP:0010851, HP:0002521, HP:0000486, HP:0000750

(Abnormal intrauterine movements, Fetal distress, Acidosis, Respiratory distress, Hypotonia, EEG with burst suppression, Hypsarrhythmia, Squint, Speech delay)

NotHPOsFreeText (neonatal, pre-treatment:) acidosis, respiratory distress, hypotonia, burst suppression on EEG, hypsarrythmia. (infancy/childhood:) recurrence of seizures with febrile illness, squint, motor problems, speech delay/difficulties, MRI changes

CasePreviousTesting Administration of pyridoxine relieved patient's seizures. CSF pipecolic acid: 0.6(nv<0.15μM), plasma pipecolic acid: 5.5, 4.9(nv<2.5μM), plasma AASA: 4.1(nv<0.2μM), urine AASA: 53(nv<1 mmol/mol creatinine).

Variant NM_001182.4(ALDH7A1):c.596C>T (p.Ala199Val), homozygous

ClinVar 17998

gnomAD not in gnomAD

CaseAddInfo 1st cousin parents

CasePMIDs n/a

CaseAC014_II-1: Female, 3 yrs report, Lebanon

CasePresentingHPOs: HP:0001992, HP:0025356 (Organic aciduria, Psychomotor retardation)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are consanguineous, Proband is confirmed homozygous for this variant via parental testing, Siblings are healthy

CasePreviousTesting: Identified by the assessment of urinary organic acids by gas chromatography–mass spectrometry; Accumulation of N-acetylated amino acids was much less pronounced than in previously reported patients

CaseGenotypingMethod: Genomic DNA was extracted either from peripheral blood or EBV-transformed lymphocytes. PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries of ACY1 was performed.

Variant: NM_000666.3(ACY1):c.1132C>T (p.Arg378Trp)

ClinVar: 493363, https://www.ncbi.nlm.nih.gov/clinvar/variation/493363/

gnomAD: 0.00001499 in ExAC, https://gnomad.broadinstitute.org/variant/3-52022996-C-T?dataset=exac

Case# P1, Pakistan,

CasePresentingHPOs reduced DHPR activity

CaseMethod1 PCR

CaseGenotypingMethod PCR

Variant NM_000320.2:c.570del

CAID CA658795210

VariantEvidence null

Case28 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 2(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 185(nv 2–14 mm/mol creatinine). In patient fibroblasts, %GCD activity was 5.

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 V400M variant creates an NlaIII site. This would lead to cleaved patient DNA fragments and uncleaved control fragments.

Variant NM_000159.3(GCDH):c.1198G>A (p.Val400Met), homozygous

ClinVar 2088

gnomAD MAF= 0.0002769(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs see note on previous studies

Cas23 sex unknown, Spain

CasePresentingHPOs n/a

HPOsFreeText Clinical onset was "insidious," involving slowly progressive psychomotor delay, dystonic postures, lethargy, or macrocephaly. Patient is otherwise phenotypically asymptomatic. 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 7932(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 1074(nv 2–14 mm/mol creatinine). In patient fibroblasts, %GCD activity was <0.5.

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 R383C variant destroys an AciI restriction site. Thus, while the patient's DNA fragments would not cleave, control fragments would be cleaved. Likewise, the 387_388del variant destroys an AluI site. This would lead to uncleaved patient DNA fragments and cleaved control fragments.

Variant 1. NM_000159.3:c.387_388del(p.Glu129AspfsTer?), 2. NM_000159.3(GCDH):c.1147C>T (p.Arg383Cys), compound heterozygous

ClinVar 1. n/a, 2. 188852

CAID 1. register link

gnomAD 1. not in gnomAD, 2. MAF= 0.00008017, no homozygotes

CaseAddInfo n/a

CasePMIDs see note on previous studies

Case7: Female, Japan, Asian

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0003798, HP:0001561, HP:0001558, HP:0000602 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Nemaline bodies, Polyhydramnios, Decreased fetal movements, Ophthalmoplegia)

HPOsFreeText: Atrophic myofibers

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Alive at 1 yr 7 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.349C>T (p.Gln117*)

CAID: CA353477271 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.349C%3ET

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1218delA (p.Lys406Asnfs*11)

CAID: CA909806380 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.1218delA

gnomAD: Not in gnomAD

Case11b: Male, Sweden

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Deceased in neonatal period

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.

Variant: NM_198271.4:c.1069G>T (p.Glu357Ter)

ClinVar: 162219 https://www.ncbi.nlm.nih.gov/clinvar/variation/162219/

gnomAD: Not in gnomAD

Case1b: Female, Algeria

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0001622 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Preterm delivery)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Deceased in neonatal period, Parents are consanguineous

CasePreviousTesting: N/A

CaseGenotypingMethod: Linkage analysis combined with homozygosity mapping was used to identify candidate chromosomal loci. Whole exome sequencing in this family revealed likely pathogenic mutations in LMOD3 which agreed with the aforementioned analysis and was consistent with autosomal recessive inheritance.

Variant: NM_198271.4(LMOD3):c.138dup (p.Ser47Glnfs)

ClinVar: 162215 https://www.ncbi.nlm.nih.gov/clinvar/variation/162215/

gnomAD: European (Non-Finnish) 8.879e-6, Overall 8.049e-6 https://gnomad.broadinstitute.org/variant/3-69171399-T-TG

Case#: Male, 3 days (onset)

CasePresentingHPOs: HP:0001250, HP:0002791, HP:0002240, HP:0001943, HP:0001942, HP:0002151, HP:0011968, HP:0003128, HP:0000648

HPOFreeText: 3 days: seizures, hypoventilation, circulatory failure, hepatomegaly, hypoglycemia, metabolic acidosis, elevated lactate. 2 months: poor feeding, somnolence, liver was normal. Developed lactic acidosis in hospital. Increased alanine, alpha-aminobutyrate, leucine, isoleucine, valine, glycine, threonine, methionine, mildy increased phenylalanine, cystathionine, cysteine, histidine. Urine analysis: increased lactic, pyruvic, and alpha-keto- and/or alpha-hydroxy-isovaleric, isocaproic, butyric, and glutaric acids. 15 months: head small (7th percentile), delayed development, progressive optic atrophy. Died at 5.5 years following acute illness.

CaseNotHPOs:

CasePreviousTesting: 3 days: metabolic acidosis (pH 7.05), and elevated lactate (12.8 mM, normal: 0.6–2.5). 2 months: lactic acidosis (10-16 mM). Increased alanine (1348 μM; normal: 132–455), α-aminobutyrate (106 μM; normal: 4–24), leucine (300 μM; normal: 61–183), isoleucine (120 μM; normal: 27–80), valine (345 μM; normal: 78–142), glycine (553 μM; normal 106–254), threonine (236 μM; normal: 65–147), methionine (151 μM; normal: 6–36).

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: E3 cDNA prepared by RT-PCR from fibroblasts of proband and parents. For proband's E3 cDNA anlaysis, 1.5kb fragment was isolated from agarose gel and transformed into E. coli, followed by sequencing of the entire E3 cDNA. Direct sequencing was performed with genomic DNA to confirm variants in proband and parents.

Variant: 1. NM_000108.4(DLD):c.1123G>A (p.Glu375Lys); 2. NM_000108.4:c.405_407del (p.Gly136del)

ClinVar: 1. 11971

CAID: 2. CA891842420

gnomAD: 1. MAF (Ashkenazi Jewish): 0.002219 (23/10366); 2. Not in gnomAD

VariantEvidence: In vitro and in vivo functional studies for the missense variant show reduced enzyme activity compared to wild type (Ambrus et al., 2011; Vaubel et al., 2011).

CaseAddInfo: E3 activity in blood lymphocytes and fibroblasts were 9% ad 3% respectively; PDC activity was 13% of controls; KGDC activity was 6% of controls. Protein levels were not changed.

CaseWG2098: 3 yrs onset

CasePresentingHPOs: HP:0001251, HP:0004302, HP:0001260, HP:0002313, HP:0012120 (Ataxia, Functional motor deficit, Dysarthria, Spastic paraparesis, Methylmalonic aciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband has normal 14C-propionate incorporation, suggesting normal MCEE protein activity level; The high gnomAD frequency and homozygotes suggests this is likely a benign polymorphism

CasePreviousTesting: Normal MRI; Propionate Incorporation w/o hydroxycobalamin at 7.0 nmols/mg protein/18hr; Propionate Incorporation with hydroxycobalamin at 8.2 nmols/mg protein/18hr; Adenosylcobalamin synthesis percentage at 12.7%; Elevated methylmalonic values of 621 µmol/mmol creatinine (reference 0.8-5.2 µmol/mmol creatinine)

CaseGenotypingMethod: Genomic DNA was extracted from patient fibroblasts, sequenced, and the three MCEE/thirteen MUT exons were analyzed and amplified. Any reported mutations were resequenced from fresh PCR product.

Variant: NM_032601.4(MCEE):c.178A>C (p.Lys60Gln)

ClinVar: 203812, https://www.ncbi.nlm.nih.gov/clinvar/variation/203812/

gnomAD: 0.01463 (10 homozygotes), https://gnomad.broadinstitute.org/variant/2-71351536-T-G

Case21 Female, 8.8yo report, Ethnicity: Italian

CasePresentingHPOs HP:0003571, HP:0012523, HP:0002013, HP:0008947, HP:0001259, HP:0002789

(propionicacidemia, oral aversion, vomiting, infantile hypotonia, coma, seizures, tachypnea)

HPOsFreeText feeding refusal, vomiting, hypotonia, coma, seizures, tachypnea, exanthema (14do). 55 IQ on Snijders-Omen Test.

CaseNotHPOs n/a

CasePreviousTesting Diagnosed by selective metabolic screen. PCC activity in patient fibroblasts was 1.1% of control.

Variant NM_000532.4(PCCB):c.562G>A (p.Gly188Arg), homozygous

ClinVar 558327

gnomAD MAF= 0.00006152(African), no homozygotes

CaseAddInfo no parental consanguinity

CasePMIDs n/a

CaseDOIII-3: Female, 12 yrs report, White

CasePresentingHPOs: HP:0001531, HP:0002020, HP:0001942, HP:0001944, HP:0002789, HP:0002013, HP:0002014, HP:0002919, HP:0012120 (Failure to thrive in infancy, Gastroesophageal reflux, Metabolic acidosis, Dehydration, Tachypnea, Vomiting, Diarrhea, Ketonuria, Methylmalonic aciduria)

HPOsFreeText: Elevated methylcitric acid

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Parents are first-cousin consanguineous, Son is healthy but second daughter shares phenotypes with the proband and shows clear methylmalonic aciduria, Proband and her sister are confirmed homozygous for this variant via parental testing

CasePreviousTesting: Serum methylmalonic acid was 1314 ng/ml (normal < 32); Vitamin B12 levels were normal (927 pg/ml, normal 200–1100); Vitamin B12 injections improved patient condition; At 12.5 yrs carnitine, plasma AAs, blood counts, and basic metabolic panels are normal but methylmalonic acid remains high at 180–1456 mmol/mol creatinine; Fibroblasts showed normal AdoCbl synthesis, contrary to expected from MMAA or MMAB variants; MUT and MMAB were sequenced with no variation found

CaseGenotypingMethod: Genomic DNA was isolated and PCR-amplified before directly sequencing all exons and flanking intronic sequences of the MCEE gene. Restriction enzyme digest confirmed the phase of the variant in the proband and the parents.

Variant: NM_032601.4(MCEE):c.139C>T (p.Arg47Ter)

ClinVar: 2343, https://www.ncbi.nlm.nih.gov/clinvar/variation/2343/

gnomAD: 0.0004884, https://gnomad.broadinstitute.org/variant/2-71351575-G-A

Case: Patient 2/ BIODEF 319, female, Caucasian, 10 days

CasePresentingHPOs: HP:0008297, HP:0040210, HP:0040206

HPOtext: Conceived by IVF. HyperPhe detected by neonatal screen, 240umol/L. Plasma Phe levels at 10 days olf was 585 umol.L. BH4 loading test normalized Phe levels. Urine levels showed high neopterin and low biopterin. PCD levels in patient's blood sample were normal. Urine reevalutation showed increased primapterin, again indicating PCD deficiency. cofactor replacement therapy was started, which improved growth trajectories on a normal diet. At 2 years old is still on diet and developing normally.

CaseNOTHPOs:

CasePreviousTesting: n/a

CaseGenotypingMethod: PCR of exons 2-4 of PCBD1 followed by direct sequencing.

Variant 1: NM_000281.3(PCBD1):c.289G>A (p.Glu97Lys)

ClinVar ID 1: 91907

Variant 2: NM_000281.3(PCBD1):c.292C>T (p.Gln98Ter)

ClinVar ID 2: 16799

compound heterozygous

gnomAD variant 1: MAF (Euro-NF)= 2.320E-5 in hets only, no homozygous. http://gnomad.broadinstitute.org/variant/10-72643733-C-T

gnomAD variant 2 n/a

AddCaseInfo: Father carries E97K variant, mother carrier of the Q98X variant, neither are symptomatic.

VariantEvidence: Expression of recombinant protein in bacteria revealed that both the E97K and Q98X variants are present in the insoluble fraction compared to wildtype which is found in the soluble. the little amount retained of each in the soluble fraction showed that they retained activity.

Patient12: 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_001159508.1:c.870_871insG

CAID: CA913184835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184835

gnomAD: n/a

CaseAHN15.1: 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(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

Variant2: NM_001003841.3:c.850G>A (p.Gly284Arg)

CAID: CA3182918, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA3182918

gnomAD: 0.00005440, https://gnomad.broadinstitute.org/variant/5-1214143-G-A

Case# Pat4, F, Chinese, 5day onset

CasePresentingHPOs HP:0008344, HP:0002013, HP:0011968, HP:0001250, HP:0001276, HP:0001279

CasePreviousTesting Tested serum BCAAs

CaseMethod1 PCR

CaseMethod2 Direct

CaseGenotypingMethod exons and flanking intronic regions of the BCKDHA, BCKDHB and DBT genes were amplified using PCR and sequenced

Variant NM_000709.3:c.178G>T, NM_000709.3:c.491T>C

CAID CA406004676(c.178), CA406010453(c.491)

CaseAddInfo mutations confirmed in parents by Sanger sequencing, Her elder brother was healthy. This patient presented with lethargy and feeding difficulty when she was 5 days old. She was admitted because of unconsciousness at the age of 5 months, and she was diagnosed with MSUD accompanied by metabolic acidosis, liver damage and hypermyotonia. Cerebral MRI showed abnormal signals in the left and right globus pallidus. Clinical improvement as well as improvement in the laboratory test results was observed after treatment. She is now 3 years and 11 months old with severe psychomotor retardation. She is still unable to walk or speak.

Case#: 3, female, 12 days (onset), 4 y (current- this differs than what is in table 1), Chinese

CasePresentingHPOs: HP: 0008344, HP: 0012088, HP:0011968, HP: 0002013, HP:0011344, HP: 0002543, HP: 0012751 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, vomiting, severe global developmental delay, abnormal globus pallidus, abnormal basal ganglia)

HPOsFreeText: Bilateral damage to capsula interna and externa, Blood ammonia: 205 uM, Hemoglobin: 118 g/L, Leucin: 891.90 uM, Valine: 502.50 uM, Isoleucine: 165.99 uM, Alloisoleucine: 90.12 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 2 different variants, unsure of cis or trans

CasePreviousTesting: n/a

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_000709.3(BCKDHA):c.178G>T (p.Glu60Ter), NM_000709.3(BCKDHA):c.1214_1219dupCCAACC (p.Asn406Leu407insProGln)

ClinVar: n/a

CAID: CA406004676 , CA658820662

gnomAD: neither in gnomAD

Case#: 6, male, 18 m (onset), 2 y 6 m (current), Chinese

CasePresentingHPOs: HP: 0008344, HP; 0012088, HP: 0011342, HP: 0001332, HP:0002543, HP: 0012751, HP:0012747 (elevated A keto acids in urine, abnormal urinary odor, mild global developmental delay, dystonia, abnormal globus pallidus, abnormal basal ganglia, abnormal brainstem MRI signal intensity)

HPOsFreeText: damage to cerebellar dentate nucleus, damage to corpora quadrigemina, damage to frontal lobe, damage to insular cortex, Isoleucine: 167.13 uM, Alloisoleucine: 44.88 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: unsure cis or trans

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_183050.3:c.767A>G (p.Tyr256Cys), NM_183050.3:c.768C>G (p.Tyr256Ter)

ClinVar: neither found

CAID: CA364659935, CA142287564

gnomAD: 0.000008820 (European, non-Finnish), not found

Case#: 8, male, 13 days (onset), 1 y 6 m (current), Chinese

CasePresentingHPOs: HP: 0008344, HP:0012088, HP:0011968, HP:0001254, HP:0002415, HP: 0006989 (elevated A keto acids in urine, abnormal urinary odor, feeding difficulties, lethargy, leukodystrophy, dysplastic corpus callosum)

FreeTextHPOs: blood ammonia: 96 uM, hemoglobin: 98 g/L, leucin: 1047.24 uM, isoleucine: 261.09 uM, alloisoleucine: 127.05 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: homozygous mutation

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_001918.3:c.1A>G (p.Met1Val)

ClinVar: not found

CAID: CA969877

gnomAD: not found

Case#: 1, male, 3 days (onset), 2 y 8 mo (current), Chinese

CasePresentingHPOs: HP:0008344 HP: 0012088, HP: 0001250, HP: 0011968, HP: 0001941, HP: 0001943, HP: 0001987, HP: 0001903, HP:0012751, HP:0002543, HP: 0001276, HP:0011343 (elevated A keto acids in urine, abnormal urinary odor, seizures, feeding difficulties, acidosis, hypoglycemia, hyperammonemia, anemia, abnormal basal ganglia MRI signal intensity, abnormal globus pallidus signals, hypertonia, moderate global developmental delay)

HPOsFreeText: Blood ammonia: 75 uM, Valine: 532.83 uM, Isoleucine: 384.90 uM, Alloisoleucine: 213.09 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: variants also found in parents

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000709.3(BCKDHA): IVS6+1delG (can't search this format of an intronic mutations, how do I change it?)

ClinVar: not sure how to search for BCKDHA IVS6 + 1delG

CAID:

gnomAD:

Variant2: NM_000709.3(BCKDHA):c.740A>G (p.His247Arg)

ClinVar: not found

CAID: CA406012849

gnomAD: not in gnomAD

There are two variants listed for every patient except, one. The text said that all the mutations found were also found in the parents so does that mean they would be in trans?

(didn't see this template at first, so still need to apply it to the other entries)

Case9 sex unknown, Netherlands, Dutch

CasePresentingHPOs HP:0001250, HP:0001263, HP:0000750

(Seizures, Psychomotor delay, Speech delay)

HPOsFreeText Seizures ceased upon administration of pyridoxine. (PMID:16159904:) 1st seizure at 3do, first administered pyridoxine(and age at trial) 8mo, initial dose:50mg, maintenance dose:50mg/day, psychomotor delay, poor language skills. (PMID:17088338:) Definite="recurrent (two or more) seizures of any type that cease within seven days of the administration of oral pyridoxine (usual dose, 30 mg/ kg/day; minimum dose, 15 mg/kg/day; maximum dose, 1000 mg/kg/day) or within 30 minutes of intravenous pyridoxine (usual dose, 100 mg; minimum dose, 50 mg), that recur when pyridoxine supplementation is withdrawn, and that cease again when pyridoxine is given as above"

CaseNotHPOs n/a

NotHPOsFreeText intrauterine seizures

CasePreviousTesting PDS confirmed metabolically: α‐AASA urine 9.6(nv <1mmol/mol cr), α‐AASA plasma 0.8(nv <0.2μmol/l), pipecolic acid urine 2.0(nv 0.55-24.1mmol/mol cr <6mo, 0.01–1.54mmol/mol cr >6 mo) pipecolic plasma 22(nv 3.75-10.8μmol/l <1wk, 0.7-2.46μmol/l >1wk)

Variant NM_001182.4(ALDH7A1):c.1279G>C (p.Glu427Gln) homozygous

ClinVar 17994

gnomAD MAF= 0.0006123(European(Non-Finnish)), no homozygotes

CaseAddInfo n/a

CasePMIDs 17088338 , 16159904

CaseCA3: Male, 6 months diagnosis

CasePresentingHPOs: HP:0001644, HP:0001875, HP:0001508, HP:0003535, HP:0003756, HP:0030319, HP:0003551 (Dilated cardiomyopathy, Neutropenia, Failure to thrive, 3-Methylglutaconic aciduria, Skeletal myopathy, Facial weakness, Difficulty climbing stairs)

HPOsFreeText: N/A

CaseNotHPOs: HP:0003107 (Abnormal circulating cholesterol concentration)

NotHPOsFreeText: N/A

CaseAddInfo: Cardiac transplant 11 months after presentation; Variant also found in mother and grandmother

CasePreviousTesting: N/A

CaseGenotypingMethod: The TAZ gene was PCR amplified in three fragments and directly sequenced in the mother and proband.

Variant: NM_000116.5(TAZ):c.589G>A (p.Gly197Arg)

ClinVar: 11105, https://www.ncbi.nlm.nih.gov/clinvar/variation/11105/

gnomAD: Not in gnomAD

Case#: Hou 2016 Proband, M, 7 days (onset), Taiwan (Amis Tribe)

CasePresentingHPOs: HP:0004396, HP:0030842, HP:0040181, HP:0002045 (continue)

HPOsFreeText:

CaseNotHPOs: .

CasePreviousTesting: Hemoglobin 1.36 mM (normal 1.4-2.17 mM); 613x10^9 platelets/L (normal 150-400x10^9); glucose 2.16 mM (normal 3.3-5.5 mM). Valine 1026 uM (normal 84.07-354 uM); leucine/isoleucine 829.41 uM (normal 56.82-287 uM).

CaseGenotypingMethod: Direct sequencing and duplex PCR of DBT.

Variant: 1. NM_001918.3(DBT):c.1282-4142_*(434_435)del; . NM_001918.3:c.650dup

ClinVar: 1. 11951

CAID: 2. CA658820832

gnomAD: 1. Not in gnomAD; Not in gnomAD

VariantEvidence: The deletion includes the 3' half of intron 10, the entire coding region of the terminal exon 11, and the 5' part of the 3' UTR of DBT.

CaseAddInfo: The 4.7 kb deletion had been previously reported in Paiwan tribe in Taiwan.

Patient5: Male, 11mo, sibling to patient 4

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 6.0 μmol l−1, IVA incorp (%) = 64, IVG in urine mmol permol creatinine = 955, Ammonium (μmol l−1) = 65, pH = 7.41, Protein intake (g kg−1 per day) = 1.5, treated with carnitine supplements, PDI/IQ in follow-up = 85

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 10 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_001159508.1:c.1214T>C

CAID: CA268781818, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781818

gnomAD: 0.000003977, http://gnomad.broadinstitute.org/variant/15-40710485-T-C

Variant2: NM_001159508.1:c.500T>C

CAID: CA391717541, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391717541

gnomAD: n/a

Case# Patient 16, Female, 2mo diagnosis

Variant NM_000320.2:c.277G>A (p.Gly93Ser)

CAID CA356450231

CaseGuA: Male, 6 weeks onset

CasePresentingHPOs: HP:0200134, HP:0020217, HP:0002069, HP:0010852, HP:0012012, HP:0012017, HP:0012018, HP:0010841, HP:0025152, HP:0030211, HP:0008936, HP:0002061, HP:0006986, HP:0002187, HP:0011344, HP:0001344, HP:0012448, HP:0002283, HP:0002079, HP:0012696, HP:0002500, HP:0012751 (Epileptic encephalopathy, Focal aware motor seizure, Bilateral tonic-clonic seizure, EEG with parietal focal spike waves, EEG with parietal focal spikes, EEG with temporal focal spikes, Multifocal epileptiform discharges, Poor visual behavior for age, Slow pupillary light response, Muscular hypotonia of the trunk, Lower limb spasticity, Upper limb spasticity, Profound intellectual disability, Severe global developmental delay, Absent speech, Delayed myelination, Global brain atrophy, Thin corpus callosum, Abnormal thalamic MRI signal intensity, White matter abnormalities, Abnormal basal ganglia MRI signal intensity)

HPOsFreeText: Dyskinetic movements of arms, In ability to sit unsupported, Abnormal MRI signal in putamen and caudate

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed heterozygous de novo

CasePreviousTesting: Investigations include electroencephalography (EEG), head MRI, neurometabolic testing, and chromosome microarray; Individuals with self-limiting benign electroclinical syndromes, such as childhood absence epilepsy (onset > 4 years), were excluded; Capture of right arm jerks and chin twitching showed no EEG correlate; Head circumference was 45.1 cm at 8 months (50%), 52 cm at 5 years (50th percentile); Partial response to phenobarbital, levetiracetam, and clobazam; Longest seizure-free period was 16 months

CaseGenotypingMethod: Variants within co-expressed candidate genes in Table S1 were extracted from exome sequencing data. Variants were annotated and were verified with Sanger sequencing of the proband and parents.

Variant: NM_004171.4(SLC1A2):c.244G>A (p.Gly82Arg)

ClinVar: 438736, https://www.ncbi.nlm.nih.gov/clinvar/variation/438736/

gnomAD: Not in gnomAD

Case5 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 7.8(nv 0.4-4.9µmol/liter), AASA in plasma 5.8(nv<0.2µmol/liter), urine AASA 28(nv<1mmol/molcreatinine). Normal urine PA after pyridoxine treatment.

Variant NM_001182.4(ALDH7A1):c.1279G>C (p.Glu427Gln), homozygous

ClinVar 17994

gnomAD not in gnomAD

CaseAddInfo n/a

CasePMIDs n/a

CaseSA1: Male, Serbia

CasePresentingHPOs: HP:0025190, HP:0001987, HP:0000825, HP:0001988, HP:0001252, HP:0025502, HP:0001263 (Generalized tonic-clonic seizure, Hyperammonemia, Hyperinsulinemic hypoglycemia, Recurrent hypoglycemia, Muscular hypotonia, Overweight, Global developmental delay)

HPOsFreeText: Born at term with a birth weight of 3850 g, birth length of 51 cm, and an Apgar score of 10

CaseNotHPOs: HP:0002353 (EEG abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy and non-consanguineous with no family history,

CasePreviousTesting: At 9 weeks blood glucose at 2.0 mmol/L, serum insulin level of 32.4 mIU/L, plasma ammonia level was of 277 μmol/L; No abnormalities in plasma amino acid levels nor in urinary organic acid concentrations

CaseGenotypingMethod: Genetic analysis was perfomed on the GLUD1 gene.

Variant: NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)

ClinVar: 16122, https://www.ncbi.nlm.nih.gov/clinvar/variation/16122/

gnomAD: Not in gnomAD

Case#: P15, F, 2 months (onset)

CasePresentingHPOs: HP:0001263, HP:0200134

CasePresentingHPOs (free text): TMS/GC-MS: Leu+Ile- 517, Val- 315. Diagnosed with intermediate form of MSUD.

CasePreviousTesting: Biochemical testing (elevated BCAAs) used to make diagnosis.

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA extracted, coding regions (and flanking exon-intron boundaries) of BCKDHA, BCKDHB, and DBT were PCR-amplified, followed by bidirectional sequencing.

Variant: NM_001918.3(DBT):c.939G>C (p.Lys313Asn) (homozygous)

ClinVar: 94017

gnomAD: MAF (South Asian) 9.747e-5

VariantEvidence: None

Case# F3-2:5, Male, Pakistan, 13mon diagnosis

CasePresentingHPOs HP:0001987, HP:0001942, HP:0001993, HP:0003128

CasePreviousTesting meningo-encephalitis (cultures were negative). Further metabolic investigations are shown in Table 1.

CaseMethod1 Sanger

CaseGenotypingMethod Sanger of CA5A exons

Variant NM_001739.1(CA5A):c.619-3421_774+502del (p.Asp207_Gln258del)

ClinVar 127089

CaseAddInfo consanguineous, heterozygous parents checked with qtPCR

Unable to annotate on article.

Case#: Konstantinidis Case 2

DiseaseAssertion: optic atrophy

FamilyInfo: none provided

CasePresentingHPOs: none, tests performed on blastocyst

CaseHPOFreeText:

CaseNotHPOs: none

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.182A > G

ClinVar: 511815

CAID: CA2758946

SupplementalData: n/a

Case#: Hudson Proband II:5, 66yo, female, UK

DiseaseAssertion: OA plus

FamilyInfo: Pedigree (Fig 1) shows 6 segregations

CasePresentingHPOs: HP:0007663, HP:0001288, HP:0001730, HP:0000746, HP:0002367, HP:0000648, HP:0000544, HP:0001488, HP:0001349, HP:0002066, HP:0001315, HP:0003236, HP:0033568, HP:0001272, HP:0002120

CaseHPOFreeText: slowly progressive deterioration in her visual acuity, a progressive gait disturbance of 20 years duration, and a 5-year history of deteriorating hearing, acute paranoid delusions, low mood, just able to perceive light, bilateral optic atrophy, plantar responses flexor, elevated serum creatine kinase (417 U/l, normal <190 U/l) with a normal fasting blood glucose and lactate, mild cortical disturbance, prominent small-vessel ischaemic lesions in the cerebral white matter bilaterally. Muscle biopsy of the index case (II:5) revealed features that were diagnostic of mitochondrial myopathy

CaseNotHPOs: HP:0001627, HP:0031983

CaseNotHPOFreeText:

PreviouslyPublished: n/a

PreviousTesting: The entire mitochondrial genome-coding region was amplified and found (m.8839G>A) in the MTATP6 gene. No sequence variants were identified in the coding region or flanking exon–intron boundaries for POLG1, PEO1, POLG2 and SLC25A4.

GenotypingMethod: The 30 coding exons and intron–exon junctions of the OPA1 gene were sequenced using a set of 30 primer pairs

Variant: c.1800C>G (p.Ser600Arg)

ClinVar: 30461

CAID: CA10575554

SupplementalData:

annotating here since this is a PDF

Case#: Yamagishi Case 2, female, 10m at dx

DiseaseAssertion: Hurler

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: mental delay. height=70cm

CaseNotHPOs: HP:0002240

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

annotating here since this is a PDF

Case#: Yamagishi Case 3, female, 3y4m at dx

DiseaseAssertion: Hurler/Scheie

FamilyInfo: Case 4 is this patient's sibling. Same genotype and similar phenotype

CasePresentingHPOs: HP:0001433

CaseHPOFreeText: height=90cm (-1.2SD)

CaseNotHPOs:

CaseNotHPOFreeText: mental delay. cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5; R89Q

ClinVar: 11921; 11922

CAID: CA256123; CA256124

SupplementalData: n/a

annotating here since this is a PDF

Case#: Yamagishi Case 1, female, 3y1m at dx

DiseaseAssertion: Hurler

FamilyInfo: consanguinity

CasePresentingHPOs: HP:0002240

CaseHPOFreeText: mental delay. height=89cm (-1.5SD)

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

Case#: KMP 1, female, 39 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA I.; ECG; echocardiography

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case#: KMP 16, female, 60 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVOTO yes; LVEF 39-40%; NYHA I.; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: Additional Sanger sequencing of exons 12, 24, 25 of MYBPC3, exon 12 NEBL, exons 12, 20, 21 of SCN5A, exon 7 of TNNI3, and exon 9 of TNNT2 gene

CaseGenotypingMethod: Sanger sequencing;

Variant: NM_000257.4(MYH7):c.2845G>A (p.Glu949Lys)

ClinVar: 14093 https://www.ncbi.nlm.nih.gov/clinvar/variation/14093/

CAID: n/a

gnomAD: absent

Case#: N5214, F, 62 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0002015, HP:0001260, HP:0002380, HP:0003690, HP:0003202

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c.1045A>T p.Thr349Ser

CAID: CA350723588

CaseAddInfo: 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#: P937, F, Italian

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing

Variant: c.19C>A p.Val7Ile

CaseAddInfo: This allele is not found in the reference NM_006000.2 or NM_006000.3 (CAID can not be created or retrieved because there is a G in this location instead of the C reported here).

CaseAddInfo: 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#: B1103, M, 57 y.o., Italian

CasePresentingHPOs: HP:0007354, HP:0003202, HP:0007340

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

Variant: NM_006000.3(TUBA4A):c.226+4A>G IVS2+4A>G

CAID: CA2018007638

CaseAddInfo: 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#: Wang Patient #7, female, 7yo at dx

DiseaseAssertion: Hurler/Scheie

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: IDUA activity=0.3 nmol/h/mg protein (normal range=27.2–52 nmol/h/mg protein.), delayed mental development, cardiac disease, Macrocephaly/joint stiffness

CaseNotHPOs:

CaseNotHPOFreeText: mongolian macula, hernia, airway obstruction

PreviouslyPublished:

Variant: p.A79V; c.1225dupG

ClinVar: 1458769;

CAID: CA356987

SupplementalData:

Case#: Wang Patient #26, female, 3yo at dx

DiseaseAssertion: Hurler

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: IDUA activity=not stated, delayed mental development, cardiac disease, Macrocephaly/joint stiffness/mongolian macula, Hepatosplenomegaly/ hernia, airway obstruction

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished:

Variant: p.A79V; 668insGCG

ClinVar: 1458769;

CAID: CA356987

SupplementalData:

Case#: Consequence 4 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2156G>A (p.Arg719Gln)

ClinVar: 14107 https://www.ncbi.nlm.nih.gov/clinvar/variation/14107/

CAID: n/a

gnomAD: absent

Case#: Consequence 6 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2146G>A (p.Gly716Arg)

ClinVar: 14105 https://www.ncbi.nlm.nih.gov/clinvar/variation/14105/

CAID: n/a

gnomAD: absent

Case#: Consequence 3 Table 1 in Data Supplement (4 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)

ClinVar: 14125 https://www.ncbi.nlm.nih.gov/clinvar/variation/14125/

CAID: n/a

gnomAD: 0.000008792 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23893321-T-C

Case#: Consequence 12 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.208A>T (p.Thr70Ser)

ClinVar: 42877 https://www.ncbi.nlm.nih.gov/clinvar/variation/42877/

CAID: n/a

gnomAD: 0.00001761 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23902430-T-A

Case#: Consequence 24 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)

ClinVar: 14089 https://www.ncbi.nlm.nih.gov/clinvar/variation/14089/

CAID: n/a

gnomAD: absent

Case#: Consequence 2 Table 1 in Data Supplement (1 case)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)

ClinVar: 36642 https://www.ncbi.nlm.nih.gov/clinvar/variation/36642/

CAID: n/a

gnomAD: 0.00004657 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23884860-C-T

Case#: Consequence 1 Table 1 in Data Supplement (1 case)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1988G>A (p.Arg663His)

ClinVar: 42875 https://www.ncbi.nlm.nih.gov/clinvar/variation/42875/

CAID: n/a

gnomAD: 0.00003097 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896042-C-T

Case#: Consequence 17 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2681A>G (p.Glu894Gly)

ClinVar: 42922 https://www.ncbi.nlm.nih.gov/clinvar/variation/42922/

CAID: n/a

gnomAD: absent

Case#: Consequence 21 Table 1 in Data Supplement (1 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.2945T>C (p.Met982Thr)

ClinVar: 42941 https://www.ncbi.nlm.nih.gov/clinvar/variation/42941/

CAID: n/a

gnomAD: 0.001416 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23892910-A-G

Case#: Consequence 18 Table 1 in Data Supplement (4 cases)

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Cardiac magnetic resonance imaging, BSA, NYHA functional class, obstructive HCM, atrial fibrillation, coronary artery disease, NSVT, Syncope, SCD family hitory, wall thickness

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Additional oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing for MYBPC3, TMP1, TNNC1, TNNI2, TNNI3, TNNT2, ACTC1, MYL3

CaseGenotypingMethod: oligonucleotide hybridization–based DNA sequencing and dideoxy-based DNA sequencing

Variant: NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg)

ClinVar: 14090 https://www.ncbi.nlm.nih.gov/clinvar/variation/14090/

CAID: n/a

gnomAD: 0.000008790 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23896932-C-G

Patients 2, 4, and 5 are all homozygous for this variant. Previously published in PMID: 22718273

Case: Fritzen Individual 2, male, German, AOR= 3 yo

CasePresentingHPOs: HP:0001511, HP:0001518, HP:0000252, HP:0000047, HP:0001643, HP:0001655, HP:0008947, HP:0001263, HP:0001344, HP:0001256, HP:0000486, HP:0000483, HP:000432, HP:0001357, HP:0000348, HP:0009890, HP:0000490, HP:0000455, HP:0000430, HP:0000343, HP:0010804, HP:0002714, HP:0012471, HP:0000047, HP:0001814, HP:0000752

CasePresentingText: intrauterine growth retardation noted at 22 weeks gestation. PFO/PDA closed spontaneously. Started walking at 18 months, at 3 years old no speech. EEG was not able to be evaluated.

CaseNOTHPOs: HP:0000365, HP:0001250

CasePreviousTesting: Chromosome analysis, microdeletion 22q11.2 testing, chromosomal microarray analysis, fragile X testing (FMR1) and methylation sensitive MLPA for chromosome 11 and 7 loci (Silver-Russell syndrome) testing were unremarkable and normal.

CaseGenotypingMethod: WES

Sanger sequencing was used to confirm the mutation and to exclude the presence of the mutant in the parents.

The WES identified a heterozygous mutation in ARID1A, a gene that is associated with Coffin-Siris syndrome. The mutation was a 6 bp duplication in (NM_006015.4:c.489_494dupCGCCGC, p.[(A164_A165dup)]. It was maternally inherited, and the mother was not noted to have behavioral abnormalities. In addition, the WES revealed 18 different mutations in 12 genes (Supplemental Table 1). Most of these were ruled out due to high frequencies in the control population in homozygoues state, or the genes were associated with disease entities that had disparate phenotypes than the those presenting in the proband.

Variant: chr2:g.48035302_48035303del; NM_001190274.1:c.2738_2739delAT (p.Y913X)

CA ID: CA658820925

de novo

gnomAD: not present

AddCaseInfo:

VariantEvidence: No variant evidence to confer alteration of FBXO11 function or pathogenicity. Furthermore, the presence of a VUS in ARID1A that is responsible for Coffin-Siris syndrome, which has many overlapping phenotype, cannot be ruled out as contributory, even in the absence of an strongly overt phenotype in the mother. Subtle behvioral phenotypes could be present, and she was not fully evaluated to rule out and behavioral abnormalities. Albeit, this mutation has arisen in another unrelated individual, de novo, in Martinez et al., 2017 (PMID: 27620904 ), as well as one patient, de novo in the DECIPHER DDD study (case 325596).Therefore, I am downgrading the score but minimally.

Case# Subject 3-1, male, 11yo, Pakistani

CasePresentingHPOs HP:0000750, HP:0011342, HP:0000286, HP:0000431, HP:0000490, HP:0000717, HP:0007302, HP:0000218, HP:0001500, HP:0001837, HP:0002650, HP:0001249, HP:0001252, HP:0000717 (Speech delay, Mild global developmental delay, Epicanthus, Broad nasal bridge, Deep set eyes, Bipolar disorder, High palate, Broad fingers, Broad toes, Scoliosis, Intellectual Disability, Hypotonia, Autism)

HPOFreeText: mild speech/motor/cognitive delay, mild prominence of lateral ventricles, mild scoliosis, mild-moderate hypotonia

CaseNotHPOs HP:0002376, HP:0001250 (Developmental regression, Seizures)

NotHPOFreeText: Ventillator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_001163435.2:c.1652T>C(p.Leu551Pro), homozygous

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

CaseAddInfo consanguinity

CasePMIDs n/a

Case# Subject 1-1, male, 5yo died, Saudi

CasePresentingHPOs HP:0001558, HP:0000750, HP:0011344, HP:0002283, HP:0006829, HP:0001250, HP:0000340, HP:0000414, HP:0010804, HP:0000582, HP:0000496, HP:0002099, HP:0000964, HP:0001249 (Decreased fetal movement, Speech delay, Severe global developmental delay, Diffuse brain atrophy, Severe hypotonia, Seizures, Sloping forehead, Bulbous nose, Tented upper lip, Upslanted palpebral fissure, Abnormality of eye movement, Asthma, Eczema, Intellectual disability)

HPOFreeText: Oligohydramnios, Abnormal white matter signal intensity, Delayed reflexes

CaseNotHPOs HP:0002376 (Developmental regression)

NotHPOFreeText: Ventilator dependence

CasePreviousTesting Variants previously reported with a minor allele frequency > 1% were excluded. WES for additional compound-heterozygous, X-linked, or heterozygous de novo variants was negative. Included in previous study based on a neurogenetic diagnosis, positive family history, consanguineous parents, and no candidate genes identified by autozygosity mapping.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES on all families, confirmed heterozygous/compound heterozygous with Sanger. Sanger on individuals with an affected family member. Parents confirmed heterozygous for childrens' variants

Variant NM_033115.4(TBCK):c.1708+1G>A, homozygous

ClinVar 183338

gnomAD 0.00006693(European(Non-Finnish)), 0.00003244(total)

VariantEvidence (Fig 2A) Western blot: TBCK expression reduced in patient fibroblasts by 78%.

CaseAddInfo Consanguinity

CasePMIDs 25558065

Case2: Female, Austria, 18 yrs report

CasePresentingHPOs: HP:0010628, HP:0002643, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0001511, HP:0001561, HP:0005216, HP:0002540, HP:0002650 (Facial weakness, Neonatal respiratory distress, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Intrauterine growth restriction, Polyhydramnios, Chewing difficulties, Non-ambulatory, Scoliosis)

HPOsFreeText: 3/3/5 Apgar score

CaseNotHPOs: HP:0002015 (Swallowing difficulties)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Whole exome sequencing of the proband revealed these homozygous LMOD3 mutations.

Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)

ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)

ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/

gnomAD: Not in gnomAD

Case3: Male, Germany, 20 yrs report

CasePresentingHPOs: HP:0010628, HP:0002015, HP:0040288, HP:0001260, HP:0003690, HP:0003798, HP:0002650 (Facial weakness, Swallowing difficulties, Nasogastric tube feeding, Dysarthric speech, Limb weakness, Nemaline bodies, Scoliosis)

HPOsFreeText: 7/8/9 Apgar score

CaseNotHPOs: HP:0002015, HP:0002540, , HP:0002098 (Swallowing difficulties, Non-ambulatory, Respiratory distress)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

CaseGenotypingMethod: Next generation sequnecing-based panel analysis detected the below variants in LMOD3.

Variant1: NM_198271.4:c.1648C>T (p.Leu550Phe)

ClinVar: 374498 https://www.ncbi.nlm.nih.gov/clinvar/variation/374498/

gnomAD: Not in gnomAD

Variant2: NM_198271.4:c.1004A>G (p.Gln335Arg)

ClinVar: 374499 https://www.ncbi.nlm.nih.gov/clinvar/variation/374499/

gnomAD: Not in gnomAD

CaseVI-4: Male, 3.5 years, Turkey

CasePresentingHPOs: HP:0004912, HP:0002540, HP:0002970 (Hypophosphatemic rickets, Inability to walk, Genu varum)

HPOsFreeText: -3.76 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 by parental testing, Proband is hemizygous for this mutation

CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.8 mg/dL; reference 3.8-6.5), Elevated serum ALP (925 IU/L; reference 90-325), 25OHD3 levels (35 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (62.2 ng/L), TPR levels (69.7), Decreased TmP/GFR levels (1.95; 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.1217G>T (p.Cys406Phe)

CAID: CA412573391 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_000444.5%3Ac.1217G%3ET

gnomAD: Not in gnomAD

Sharkia Proband A-3, onset at 5 weeks old, 5yo at report, Caucasian, American, male. Patient A3 has

Variant: c.590A>G and c.172C>T

CaseHPO: HP:0001252, HP:0001251, HP:0001250, HP:0002120, HP:0001272, HP:0000648, HP:0000512, HP:0012736, HP:0001508, HP:0000252, HP:0030890

Case# P7, 2yo report

CasePresentingHPOs HP:0005528, HP:0001873

CasePreviousTesting genes related to MDS/inherited bone marrow failure syndromes was performed in patients, negative for this patient

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo transient monosomy 7 with somatic mutation of new variant NM_152703.3:c.3951_3955del (p.Ser1317ArgfsTer21) - CA658820702

Case# P5, 7yo report

CasePresentingHPOs HP:0005528, HP:0001873

CasePreviousTesting genes related to MDS/inherited bone marrow failure syndromes was performed in patients, negative for this patient

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys)

ClinVar 446530

VariantEvidence (Figure 5) 293FT cells transfected with p.Arg986Cys showed more limited cell proliferation than WT SAMD9L in 28202457

CaseAddInfo "The HLA-identical brother of P5 was thoroughly evaluated as a potential bone marrow donor. He was clinically healthy and had a normal complete blood count, but he did not qualify as a donor because of hypocellular bone marrow with mild dysplastic features. He was also a carrier of the p.R986C mutation."

Case1: Male, 3 months onset, Australia

CasePresentingHPOs: HP:0002878, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0003691, HP:0003391, HP:0003803, HP:0003755 (Respiratory failure, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Scapular winging, Gowers sign, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: BiPAP from 3.5 yrs, Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Internally nucleated skeletal muscle fibers)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmed

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.733A>G (p.Arg245Gly)

ClinVar: 42117 https://www.ncbi.nlm.nih.gov/clinvar/variation/42117/

gnomAD: Not in gnomAD

Case2: Male, Birth onset, Australia

CasePresentingHPOs: HP:0008947, HP:0002460, HP:0001270, HP:0003701, HP:0000467, HP:0001488, HP:0002938, HP:0010628, HP:0003391, HP:0002942, HP:0003803, HP:0003755 (Infantile muscular hypotonia, Distal muscle weakness, Motor delay, Proximal muscle weakness, Neck muscle weakness, Bilateral ptosis, Lumbar hyperlordosis, Facial palsy, Gowers sign, Thoracic kyphosis, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Type 2B fibers absent

CaseNotHPOs: HP:0003798, HP:0030177, HP:0030877, HP:0031237 (Nemaline bodies, Abnormal nerve conduction study, Obstructive deficit on pulmonary function testing, Internally nucleated skeletal muscle fibers)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmation

CasePreviousTesting: Patients were diagnosed with CFTD via clinical notes and muscle biopsies at pathology centers throughout Australia and several international centers.

CaseGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. Paternity was confirmed in isolated patients using microsatellite markers.

Variant: NM_152263.4(TPM3):c.505A>G (p.Lys169Glu)

ClinVar: 42115 https://www.ncbi.nlm.nih.gov/clinvar/variation/42115/

gnomAD: Not in gnomAD

Case9 Male, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001829, HP:0010066, HP:0000157, HP:0002101, HP:0002324, HP:0010664, HP:0030449

(Oral cleft, Micrognathia, Hand polydactyly, Duplicated hallux, Tongue abnormality, Defective lung lobation, Hydranencephaly, Fused thalami, Therapeutic abortion)

HPOsFreeText Crown-heel body length 22cm, body weight 245g, brain weight 6g, abnormal larynx/trachea, occipitoschisis/keyhole, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, duplicated central canal in lumbar spinal cord, posterior columns seem disorganized. The ventral horn shows normal-appearing motor neurons with an SMI-311 neurofilament immunostain.

CaseNotHPOs HP:0001161

(Hand polydactyly)

NotHPOsFreeText Uterus duplex, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 19+5wk gestational age

CasePMIDs n/a

Case14 Female, Finland

CasePresentingHPOs HP:0000347, HP:0001829, HP:0010066, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260

(Micrognathia, Foot polydactyly, Duplicated hallux, Defective lung lobulation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)

HPOsFreeText Crown-heel body length 35.5cm, body weight 1162g, brain weight 153g, abnormal larynx/trachea, uterus duplex, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia in the Sylvian fissures , neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, large hypothalamic hamartoma that covers the brainstem (Fig4:) consisting of slightly nodular areas of small, round, probably partly immature, neuronal, and possibly some oligodendroglial cells, capillaries, astroglial cells, and occasional larger pyramidal neuronal cells on hematoxylin and eosin stain.

CaseNotHPOs HP:0000202, HP:0001627, HP:0000157, HP:0007165

(Oral cleft, Congenital heart defect, Tongue abnormality, Periventricular neuronal heterotopia)

NotHPOsFreeText hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo death at 20 minutes old, 33+5wk gestational age

CasePMIDs n/a

Case8 Male, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001829, HP:0010066, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Oral cleft, Micrognathia, Foot polydactyly, Duplicated hallux, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Therapeutic abortion)

HPOsFreeText Crown-heel body length 20cm, Body weight 323g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001161, HP:0000157, HP:0007165

(Hand polydactyly, Tongue abnormality, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, leptomeningeal heterotopia, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 19+0wk gestational age

CasePMIDs n/a

Case3 Female, Finland

CasePresentingHPOs HP:0000347, HP:0010066, HP:0001829, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007165, HP:0030449

(Micrognathia, Duplicated hallux, Foot polydactyly, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Periventricular neuronal heterotopia, Therapeutic abortion)

HPOsFreeText crown-heel body length 17cm, body weight 103g, abnormal larynx/trachea, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, hydrocephalus/open-book, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001627, HP:0000157, HP:0007260

(Oral cleft, Congenital heart defect, Tongue abnormality, Type II lissencephaly)

NotHPOsFreeText Uterus duplex, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 15+6wk gestational age

CasePMIDs n/a

Case18 Male, Finland

CasePresentingHPOs HP:0003826, HP:0000347, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260

(Stillbirth, Micrognathia, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly)

HPOsFreeText Crown-heel bodylength 45cm, body weight 2050g, brain weight 265g, abnormal larynx/trachea, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001161, HP:0001829, HP:0007165

(Oral cleft, Hand polydactyly, Foot polydactyly, Periventricular heterotopia)

NotHPOsFreeText Uterus duplex, neuroepithelial rosettes, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo stillbirth, 36+6wk gestational age

CasePMIDs n/a

Case5 Male, Finland

CasePresentingHPOs HP:0000347, HP:0001161, HP:0001829, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

(Micrognathia, Hand polydactyly, Foot polydactyly, Tongue abnormality, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Therapeutic aboriton)

HPOsFreeText Crown-heel body length 22cm, body weight 315g, Toe polydactly with multiple extra toes, Abnormal larynx/trachea, Hydrocephalus/open-book, Occipitotemporal hypoplasia, Infratentorial hypoplasia, occipitotemporal hypoplasia, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001627, HP:0002444, HP:0007165

(Oral cleft, Congenital heart defect, Hypothalamic hamartoma, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hypothalamic hamartoma/bulging, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo induced abortion at 18+1wk gestational age

CasePMIDs n/a

Case13 Female, 6day old death, Finland

CasePresentingHPOs HP:0000347, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0007165

(Micrognathia, Tongue abnormality, Defective lung lobulation, Hydrocephalus, Olfactory lobe aplasia, Callosal aplasia, Fused thalami, Polymicrogyria, Type II lissencephaly, Periventricular neuronal heterotopia)

HPOsFreeText Crown-heel body length 42cm, Body weight 2326g, brain weight 206g, abnormality larynx/trachea, uterus duplex, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, small unilateral remnant of the olfactory tract, (Fig2:)small proximal stumps of callosal fibers with a small longitudinal Probst bundle element, lateral periventricular nodular heterotopia, smooth cortical surface without normal gyration; missing midline commissures , large leptomeningeal heterotopia between the ba and brain tissue surface immunopositive for microtubule-associated protein 2 (MAP-2), hypoplastic temporal lobe displays a miniature dentate fascia, dysplastic hippocampus, heterotopic (Fig5:) glioneuronal wart-like eruption, irregular and disrupted bundles of radial glial structures, calretinin (CR)-positive and reelin positive neurons in dysplastic cortex, (Fig6:) minute dysplastic inferior olive only in some neuronal groups, totally narrowed pyramid medially below in the right lower corner of the medulla oblongata, all layers are narrowed in the atrophic cerebellar cortex of HLS, short and small frontal bundle of Probst

CaseNotHPOs HP:0000202, HP:0001829, HP:0001627

(Oral cleft, Foot polydactyly, Congenital heart defect)

NotHPOsFreeText true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

Variant NM_145014.2(HYLS1):c.632A>G (p.Asp211Gly), homozygous

ClinVar 1143

gnomAD MAF= 0.009594(European(Finnish)), no homozygotes

CaseAddInfo 33+5wk gestational age

CasePMIDs n/a

Case# Fam2:II-4, M, 7yo onset, Finnish

CasePresentingHPOs HP:0001310, HP:0001260, HP:0001251, HP:0000639, HP:0009072, HP:0008969, HP:0003487

CaseMethod1 WES

Variant NM_152703.4(SAMD9L):c.2672T>C (p.Ile891Thr)

ClinVar 446529

CaseAddInfo previously in 28202457

Case# UW-AP:III-3, 60yo reported

CasePresentingHPOs HP:0001251, HP:0001310, HP:0001260, HP:0000639, HP:0007256

Variant NM_152703.4(SAMD9L):c.2640C>A (p.His880Gln)

ClinVar 242372

CaseAddInfo only genotyping methods described are for extended Family 1 or in a previous study. Is this UW family also from another study?

Case# Subject 3, F, 5mo onset, Hispanic

CasePresentingHPOs HP:0002910, HP:0001942, HP:0003201, HP:0001664, HP:0002878, HP:0001663, HP:0001249, HP:0001250, HP:0008619, HP:0100295, HP:0001260, HP:0004756, HP:0001259, HP:0012734, HP:0002151, HP:0003236, HP:0002307, HP:0000252, HP:0004322, HP:0004325, HP:0002058, HP:0002136

HPOcont: Elevated Transaminases, Metabolic acidosis, Rhabdomyolysis, Torsade de pointes, Respiratory Failure, Ventricular fibrillation, Intellectual Disability, Seizures, Bilateral sensorineural hearing impairment, Muscle fiber atrophy, Dysarthria, Ventricular tachycardia, Coma, Ketotic hypoglycemia, Elevated Lactate, Elevated CPK, Drooling, Microcephaly, Short Stature, Low body weight, Myopathic facies, Broad-based gait

HPOFreeText: (5 months) coma, metabolic acidosis and rhabdomyolysis. (24 years) torsade de pointes, respiratory and multiorgan failure, ventricular fibrillation, epilepsy, bilateral sensorineural hearing loss, intellectual disability and atrophic muscle fibers. She was ambulatory, some speech, drooling, myopathic facies, and wide-based gait. "Height and weight below the 5th percentile for age (weight 42.9 kg, height 147 cm), head circumference below 5th percentile for age (51.4 cm)."

CaseNotHPOs HP:0002540, HP:0001987

NotHPOcont: Non-ambulatory, Hyperammonemia

CasePreviousTesting CPK elevated to 8,000 U/I on first episode, then 22,000 U/I during most severe episode.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES and cSNP results confirmed with Sanger

Variant (1) NM_152906.6:c.460G>A (p.Gly154Arg)

ClinVar (1) 208823

CAID (1) CA358646

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

VariantEvidence (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, parents confirmed heterozygotes

CasePMIDs n/a