Likely Variant Evidence for Variant: c.466C>T (p.Arg156Ter) ClinVar: 39743 and Variant:c.222del (p.Met74IlefsTer15) CAID: CA891862642

Case12: Female, Chinese, 1.5 y (end of study)

HPOsFreeText: 11 mo onset, poor neruological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case 12 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant2: NM_000255.3:c.2179C>T (p.Arg727Ter)

ClinVar: 218998

CAID: CA347913

gnomAD: 0.0001504 (East Asian)

CaseAddInfo: heterozygous mutations in trans

Case11: Female, Chinese, 2 y (age at death)

HPOsFreeText: 9 mo onset, responsive to vitamin B12

Case11 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant2: NM_000255.3:c.1514T>C (p.!le505Thr)

ClinVar: n/a

CAID: CA364397174

gnomAD: n/a

CaseAddInfo: heterozygous mutations in trans, died at 2 y

Case10: Male, Chinese, 6.4 y (onset)

HPOsFreeText: 6.4 y onset

NotHPOsFreeText: not responsive to vitamin B12

Case10 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant2: NM_000255.3:c.729_730insTT (p.Asp244LeufsTer?)

ClinVar: 552079

CAID: CA3847064

gnomAD: 0.0002008 (East Asian)

CaseAddInfo: lost to follow up, heterozygous mutations in trans

Case13: Female, Chinese, 7 mo (onset)

HPOsFreeText: 7 mo onset

NotHPOsFreeText: not responsive to vitamin B12

Case13 (Level 2):

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.419T>C (p.Leu140Pro)

ClinVar: n/a

CAID: CA364404765

gnomAD: n/a

Variant2: NM_000255.3:c.424A>G (p.Thr142Ala)

ClinVar: n/a

CAID: CA364404758

gnomAD: n/a

CaseAddInfo: Variant 1 is novel. Heterozygous mutations in trans. lost to follow up.

Case1: Male, Chinese, 1.8 y (end of study)

HPOsFreeText: neonatal onset, poor neurological outcome

NotHPOsFreeText: not responsive to vitamin B12

Case9 (Level 2)

CasePreviousTesting: same as group

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)

Variant2: NM_000255.3(MMUT):c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

Variant3: NM_000255.3:c.2168G>A (p.Gly723Asp)

ClinVar: n/a

CAID: CA3846630

gnomAD: 0.00006533 (South Asian)

CaseAddInfo: Variant 1 in trans to Variants 2 and 3 (cis). Variant 3 is novel

Case8: Male, Chinese, 8 mo (onset)

HPOsFreeText 8 mo onset, responsive to vitamin B12

Case8 (Level 2)

CasePreviousTesting: same as group

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)

Variant2: NM_000255.3:c.567T>G (p.Asn189Lys)

ClinVar: 618734

CAID: CA364404447

gnomAD: n/a

CaseAddInfo: lost to follow up, heterozygous mutations in trans

Case7: Male, Chinese, 33 d (age at death)

HPOsFreeText: Neonatal onset

NotHPOsFreeText: Not responsive to vitamin B12

Case7 (Level 2)

CasePreviousTesting: Same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.103C>T (p.Gln35Ter)

ClinVar: n/a

CAID: CA364405751

gnomAD: 0.00009950 (Ashkenazi Jewish)

Variant2: NM_000255.3:c.494A>G (p.Asp165Gly)

ClinVar: n/a

CAID: CA138799926

gnomAD: 0.00005443 (East Asian)

CaseAddInfo: died at 33d, heterozygous mutations in trans

Case6: Female, Chinese, 1 mo (onset)

HPOsFreeText: not responsive to vitamin B12

Case6 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000255.3:c.68C>G (p.Ser23Ter)

ClinVar: n/a

CAID: CA364405860

gnomAD: n/a

Variant2: NM_000255.3:c.323G>A (p.Arg108His)

ClinVar: 100707

CAID: CA235522

gnomAD: 0.00006152 (African)

CaseAddInfo: lost to follow up, heterozygous mutations in trans

CaseEG1291: Female, 5 days onset

CasePresentingHPOs: HP:0200134, HP:0012469, HP:0032794, HP:0032667, HP:0002187, HP:0032792, HP:0002069, HP:0007359, HP:0010841, HP:0002188, HP:0006913, HP:0002079, HP:0001290 (Epileptic encephalopathy, Infantile spasms, Myoclonic seizure, Myoclonic status epilepticus, Profound intellectual disability, Tonic seizure, Bilateral tonic-clonic seizure, Focal-onset seizure, Multifocal epileptiform discharges, Delayed CNS myelination, Frontal cortical atrophy, Hypoplasia of the corpus callosum, Generalized hypotonia)

HPOsFreeText: N/A

CaseNotHPOs: HP:0002521 (Hypsarrhythmia)

NotHPOsFreeText: N/A

CaseAddInfo: Proband confirmed de novo heterozygous by parental sequencing; Father had two seizures as an adult, no further seizures while on LTG

CasePreviousTesting: Currently on levitiracetam and valproate; previously on pyridoxine, prednisolone, vigabatrin, zonisamide and ketogenic diet

CaseGenotypingMethod: About 10% of the original 290 genes where a single de novo variant had been identified was chosen for targeted sequencing in a new cohort. Most of these individuals had been tested for mutations of known and novel candidate genes as well as pathogenic copy-number variants. These genes were sequenced in the parents and proband to look for de novo variants.

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

ClinVar: 254265, https://www.ncbi.nlm.nih.gov/clinvar/variation/254265/

gnomAD: Not in gnomAD

Case8: Female, South America

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.

Variant1: NM_198271.4:c.723_733del (p.Asp242Glufs*4)

CAID: CA2488932 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.723_733del

gnomAD: Latino 2.896e-4, Overall 4.416e-5 https://gnomad.broadinstitute.org/variant/3-69168772-AAGCTCCCATCC-A

Variant2: NM_198271.4:c.976G>C (p.Gly326Arg)

CAID: CA353473660 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_198271.4%3Ac.976G%3EC

gnomAD: Not in gnomAD

Case9: Female, Italy

CasePresentingHPOs: HP:0001290, HP:0003324, HP:0002093, HP:0011968, HP:0001283, HP:0003798, HP:0001561, HP:0001558, HP:0000602, HP:0001622, HP:0001371 (Generalized hypotonia, Generalized muscle weakness, Respiratory insufficiency, Feeding difficulties, Bulbar weakness, Nemaline bodies, Polyhydramnios, Decreased fetal movements, Ophthalmoplegia, Preterm delivery, Contractures)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Severe congenital myopathy, Deceased in 4 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.

Variant: NM_198271.4:c.860delT (p.Phe287Serfs*3)

CAID: CA913203455 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203455

gnomAD: Not in gnomAD

FamilyBI3: N/A

FamilyPresentingHPOs: HP:0001875, HP:0001644, HP:0003756 (Neutropenia, Dilated cardiomyopathy, Skeletal myopathy)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Five genes noted to have high heart and skeletal muscle expression were sequenced and ORFs created. After PCR amplification and direct sequencing of the TAZ gene (G4.5.), each family was seen to have a unique variant that segregated with the disease.

FamilyPreviousTesting: N/A

FamilyAddInfo: N/A

Variant: NM_000116.5(TAZ):c.239-1G>A

ClinVar: 11100, https://www.ncbi.nlm.nih.gov/clinvar/variation/11100/

gnomAD: Not in gnomAD

Affected: 2

Unaffected: 3

Segregations: 4

AddSegregationInfo: Candidate gene sequencing

CaseOS-152_II-1: Female, 1 yr report, United Kingdom

CasePresentingHPOs: HP:0001992, HP:0002013, HP:0002013, HP:0040293, HP:0010628, HP:0007359 (Organic aciduria, Vomiting, Bilateral tonic-clonic seizure, Right hemiplegia, Facial palsy, Focal-onset seizure)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001263 (Global developmental delay)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are non-consanguineous, Proband is confirmed compound heterozygous for these variants via parental testing, R353C variant inherited from father but R393H supposedly de novo or mosaic

CasePreviousTesting: Routine urine screening for organic acidurias by gas chromatography–mass spectrometry showed markedly increased urinary excretion of several N-acetylated amino acids; Normal cranial imaging

CaseGenotypingMethod: PCR-amplification and bidirectional sequencing of all exons and exon-intron boundaries was performed on genomic DNA.

Variant1: NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)

ClinVar: 18110 https://www.ncbi.nlm.nih.gov/clinvar/variation/18110/

gnomAD: 0.004135 (4 homozygotes), https://gnomad.broadinstitute.org/variant/3-52022837-C-T

Variant2: NM_000666.3(ACY1):c.1178G>A (p.Arg393His)

ClinVar: 18114 https://www.ncbi.nlm.nih.gov/clinvar/variation/18114/

gnomAD: 0.006571 (3 homozygotes), https://gnomad.broadinstitute.org/variant/3-52023042-G-A

Case 8 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

__

Variant1: NM_015506.2(MMACHC):c.394C > T (p.Arg132Ter)

ClinVar: 1423

CAID: CA251787

gnomAD: 0.0007190 (South Asian)

__

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

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier of p.R132X maternal variant

Case 9 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: PCR

CaseGenotypingMethod: same as group

__

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

ClinVar: 30800

CAID: CA259906

gnomAD: 0.0005562 (East Asian)

Variant2: NM_015506.2(MMACHC):c.637G>T (p.Glu213Ter)

ClinVar: n/a

CAID: CA340133779

gnomAD: n/a

CaseAddInfo: proband genotype, unknown cis or trans, no phenotypic info, sibling (fetus) carrier of p.W203X maternal variant

Case1: Female, 9 days at follow up, North African ancestry

CasePresentingHPOs: HP:0002013, HP:0001944,HP:0031123, HP:0000388 (emesis, dehydration, recurrent gastroenteritis, otitis media)

HPOsFreeText: NBS C4-acylcarnitine 2.9 umol/L, plasma C4 acylcarnitine 1.35 umol/L, isoC4-acylcarnitine 0.090 umol/g protein,

CaseNotHPOs:

NotHPOsFreeText: normal urine isobutyrylglycine

CaseAddInfo: repeatedly hospitalized during first 2 years of life.

CasePMIDs:

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant: NM_014384.2(ACAD8):c.988C>T (p.Arg330Trp)

ClinVar: 5357

CAID: CA117438

gnomAD: 0.00006155 (African)

CaseAddInfo: homozygous mutations

FamilyHA: White, Great Britian

FamilyPresentingHPOs: HP:0000988, HP:0002344, HP:0002359, HP:0002355, HP:0007210, HP:0000712, HP:0002066, HP:0000639, HP:0001347, HP:0008353 (Skin rash, Progressive neurologic deterioration, Frequent falls, Difficulty walking, Lower limb amyotrophy, Emotional lability, Gait ataxia, Nystagmus, Hyperreflexia, Neutral hyperaminoaciduria)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Homozygosity mapping and fine mapping in ten members of two consanguineous families (the siblings in whom Hartnup disorder was originally discovered; family A) and in siblings from the US revealed linkage of Hartnup disorder to 5p15 only in family A, with a maximum combined multipoint lod score of 2.31 at 11.24 cM. This confirmed a previous study showing linkage to the same region. Both SLC6A18 and SLC6A19 were investigated for possible pathogenicity, with SLC6A19's pattern of expression supporting it as a primary candidate. Intronic primers were used to bidirectionally sequence each exon and flanking intronic regions, locating a homozygous splice site mutation that perfectly segregated with the phenotype.

FamilyPreviousTesting: Consistent testing showed the consistent phenotypes were the hyperaminoaciduria among all family members; Linkage analysis for SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A20 were all negative for amy correlation

FamilyAddInfo:

FamilyProband: Case EHAA

FamilyPMIDs: 13358233

Variant: NM_001003841.3(SLC6A19):c.1173+2T>G

ClinVar: 449553 https://www.ncbi.nlm.nih.gov/clinvar/variation/449553/

gnomAD: 0.00008019, https://gnomad.broadinstitute.org/variant/5-1217062-T-C?dataset=gnomad_r2_1

Affected: 4

Unaffected: 5

pLOD: 2.31 at 11.24 cM

AddSegregationInfo: Family is consanguineous (first cousins), Candidate gene sequencing, Pedigree in Figure 1aA

Case5 Female, 6yo diagnosis, Korean

CasePresentingHPOs HP:0001083, HP:0003235

(Ectopia lentis, Increased blood methionine)

HPOsFreeText pretreatment homocysteine was normal, increased post-treatment total homocysteine, patient treated with low-methionine diet, vitamin B6, folate, vitamin B12, and betaine after diagnosis

CaseNotHPOs HP:0001249

(Intellectual disability)

NotHPOsFreeText Marfan syndrome, vascular occlusion

CasePreviousTesting pretreatment/posttreatment methionine: 697/648 μM(nv 7-47), pretreatment homocysteine: 3 μM(nv 0-5), posttreatment total homocysteine 121 μM(nv 5-15)

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified all 16 coding exons of CBS gene, then direct sequenced

Variant 1. NM_001178008.1:c.464C>T(p.Ala155Val), 2. NM_000071.2(CBS):c.1039G>A (p.Gly347Ser), compound heterozygous

ClinVar 1. n/a, 2. 188801

CAID 1. CA410601498

gnomAD 1. not in gnomAD, 2. MAF=0.00006497(European(non-Finnish)), no homozygotes

CaseAddInfo A155V inherited from father, G347S from mother

CasePMIDs n/a

FamilyLabel Family 15

Family15PresentingHPOs n/a

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Anglo-Celtic

Race n/a

Family15PreviousTesting 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.

FamilyMethod1 PCR

FamilyMethod2 Sanger

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

ProbandLabel Case 18

Variant NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

Case29 Male, 1yo diagnosis (Family 25)

CasePresentingHPOs HP:0001256, HP:0001263

(Mild intellectual disability, Developmental delay)

HPOsFreeText Diagnosed was on the basis of developmental delay. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs n/a

NotHPOsFreeText no other sequelae

CasePreviousTesting n/a

Variant 1. NM_000071.2(CBS):c.536_553del18 (p.Asp179_Leu184del), 2. NM_000071.2(CBS):c.325T>C (p.Cys109Arg), comp het

ClinVar 1. 198388, 2. 212878

gnomAD 1. MAF=0.00002683(European(non-Finnish), no homozygotes, 2. MAF= 0.0001631(Other), no homozygotes

CaseAddInfo son of patient 30

CasePMIDs n/a

FamilyLabel Family 26

Family26PresentingHPOs HP:0001083

(Lens dislocation)

HPOsFreeText Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Affected individuals were not responsive to the treatment, plasma homocysteine levels went unchanged. Patients were given additional oral betaine(3g twice per day) with a low protein diet.

FamilyNotHPOs n/a

NotHPOsFreeText n/a

CountryOrigin n/a

Ethnicity Portugese

Race n/a

Family26PreviousTesting 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.

FamilyMethod1 PCR

FamilyMethod2 Sanger

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

ProbandLabel Case 31

Variant NM_000071.2(CBS):c.374G>A (p.Arg125Gln), homozygous

ClinVar 197625

gnomAD MAF= 0.00002326(European(non-Finnish)), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

Case25 9yo diagnosis, Australia, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0002342, HP:0000939, HP:0001263, HP:0001369

(Lens dislocation, Moderate intellectual disability, Osteoporosis, Developmental delay, Arthritis)

HPOsFreeText Patient had severe osteoporosis, juvenile arthritis and was diagnosed on the basis of dislocated lenses and developmental delay. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. Patient was not responsive to the treatment, plasma homocysteine levels went unchanged. Patient was given additional oral betaine(3g twice per day) with a low protein diet

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting Free homocystine, methionine, cystine, and cysteine-homo-cysteine mixed disulfide levels were measured by amino acid analyzers and total (free plus bound)homocysteine (tHcys) was measured. Exact values were not provided. (PMID:9156316): Total homocysteine was 252μmol/l before and 34μmol/l after treatment of betaine, folic acid, and low-dose aspirin.

CaseMethod1 PCR

CaseMethod2 Sanger

CaseGenotypingMethod PCR amplified then direct sequenced the entire coding region of CBS. (PMID: 9156316): Restriction analysis confirmed the presence of two variants. The variant c.430G>A destroys a TaqI site. Thus, TaqI digestion yielded uncleaved 155bp fragments in both the proband and his father, while the WT was cleaved into 107 and 48bp fragments. The c.1316G>A variant likewise destroys a HapII site. The proband and his father had uncleaved 120bp fragments while the WT had 87 and 33bp fragments on HapII digestion. As both variants were detected in the proband, father, and two paternal aunts, c.1316G>A and c.430G>A were proposed to be in cis.

Variant 1. NM_000071.2:c.892dup (p.Gln298ProfsTer?), 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. n/a, 2. 122; 3. 189088

CAID 1. register

gnomAD 1. MAF=0.00001777(European(Non-finnish)), no homozygotes 2. MAF=0.00009799(South Asian), no homozygotes, 3. MAF=0.00005341(African), no homozygotes

CaseAddInfo n/a

CasePMIDs 9156316

Case15 3yo diagnosis, Anglo-Celtic

CasePresentingHPOs HP:0001083, HP:0001256

(Lens dislocation, Mild intellectual disability)

HPOsFreeText Diagnosis was based on dislocated lens and intellectual disability. Treatment began with 100-200mg/day for two weeks followed by an addition of 5mg/day folic acid. This patient was not responsive to the treatment, plasma homocysteine levels went unchanged. This patient was given additional oral betaine(3g twice per day) with a low protein diet.

CaseNotHPOs n/a

NotHPOsFreeText no other sequelae

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 NM_000071.2(CBS):c.919G>A (p.Gly307Ser), homozygous

ClinVar 117

gnomAD MAF= 0.00041539(Other), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

FamilyLabel Family 1

Family1PresentingHPOs HP:0001083, HP:0000545, HP:0000501, HP:0001249, HP:0001260, HP:0001251, HP:0007256, HP:0000577, HP:0002317, HP:0007663, HP:0030854)

(Ectopia lentis, Myopia, Glaucoma, Intellectual disability, Dysarthria, Ataxia, Pyramidal signs, Exotropia, Gait instability, Poor visual acuity, Staphyloma)

HPOsFreeText skeletal deformities, malar flush, increased serum homocysteine and methionine, corneal staphyloma, biocular lens dislocation

FamilyNotHPOs n/a

CountryOrigin China

Ethnicity n/a

Race n/a

Family1PreviousTesting Screened for variants MTHFR by PCR amplifying its coding sequence. No variants were detected in MTHFR. Also measured metabolite levels of homocysteine and methionine in plasma, both were elevated in affected individuals

FamilyMethod1 PCR

FamilyMethod2 Sanger

FamilyGenotypingMethod Coding sequences of both MTHFR and CBS were PCR amplified and Sanger sequenced detecting no variants in MTHFR. Sequence primers for CBS were designed from flanking sequences of each exon.

ProbandLabel III:3

Variant 1. NM_001178008.1:c.407T>C(p.Leu136Pro), 2. NM_001178008.1:c.473C>T(p.Ala158Val), compound heterozygous

ClinVar n/a

CAID 1. CA321097579, 2. CA410601473

gnomAD 1. MAF=0.000008809(European(non-Finnish)), no homozygotes, 2. MAF=0.00004164(South Asian), no homozygotes

FamilyAddInfo parents, grandparents and other relatives were asymptomatic for homocystinuria. A158V variant inherited from father(II:3), L136P from mother(II:4). Han Chinese

FamilyPMIDs n/a

CaseHE9: 6 month onset

CasePresentingHPOs: HP:0001250, HP:0001943, HP:0001942, HP:0012120 (Seizure, Hypoglycemia, Metabolic acidosis, Methylmalonic aciduria)

HPOsFreeText: Elevated proionyl-carnitine and methyl-citrate in urine

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is homozygous for this variant,

CasePreviousTesting: Fibroblast cell lines taken from 150 patients with mild but clear MMAuria were studied; Urinary MMA at 143–184 mmol/mol creat. (ref 0.3-1.1); Low propionate incorporation in fibroblasts both +/- OHCbl of 3.0 nmol/16 h/mg (ref 3.5–24.4 −OHCbl, 4.3–28.9 +OHCbl); Not responsive to Vitamin B12 treatment

CaseGenotypingMethod: Genomic DNA and RNA extraction was performed and the MCEE gene was sequenced to identify any likely pathogenic variants.

Variant: NM_032601.3:c.158T>G (p.Ile53Arg)

CAID: CA347189175, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA347189175

gnomAD: Not in gnomAD

Case34 female, 5.5yo report, Ethnicity: German

CasePresentingHPOs HP:0003571, HP:0012523, HP:0001531, HP:0002791, HP:0001944

(propionicacidemia, oral aversion, failure to thrive in infancy, bradypnea, dehydration)

HPOsFreeText feeding refusal, failure to thrive, bradypnea, dehydration(2do). 55 IQ on Culture Free Test

CaseNotHPOs n/a

CasePreviousTesting Diagnosed on newborn screen. PCC activity in patient fibroblasts was 0.9% of control

Variant NM_000532.4:c.483dup (p.Gly162TrpfsTer?), homozygous

ClinVar n/a

CAID to register

gnomAD not in gnomAD

CaseAddInfo no parental consanguinity

CasePMIDs n/a

Case1: Female, 1y 7m, Chinese

HPOsFreeText: (at 13 days) C4 1.31 umol/L, C4/C2 0.21, C4/C3 1.96

NotHPOsFreeText: normal urine isobutyrylglycine

Case1 (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

Variant1: NM_014384.2:c.235C>G (p.Arg79Gly)

ClinVar: n/a

CAID: CA6372884

gnomAD: 0.0002718 (East Asian)

Variant2: NM_014384.2:c.1000C>T (p.Arg334Cys)

ClinVar: n/a

CAID: CA6373194

gnomAD: 0.0003007 (East Asian)

CaseAddInfo: trans heterozygous, inherited one allele from each parent

Case: B.E./ BIODEF 272, male, 3 weeks

CasePresentingHPOs: HP:0008297, HP:0001252, HP:0001270

HPOText: Neonatal (3 days old) plasma screen showed Phe levels at 183 umol/L, which is below the normal cutoff. Repeat screen was only performed at 3 weeks old in which the Phe level was shown to be 1600 umol/L. Peak Phe level was at 3.5 weeks and was 2589 umol/L. Child had considerable Phe tolerance ( ~100mg/kg). Initial neopterin-to-biopterin ratio of 15. A BH4-loading test (6 mg/kg) at age 6 wk showed only a slight response (Phe at 0 h, 731 μmol/liter; at 3 h, 612 μmol/liter; and at 6 h, 502 μmol/liter). A week later, at a BH4 dose of 22 mg/kg, there was a definite response (Phe at 0 h, 773 μmol/liter; at 3 h, 517 μmol/liter; and at 6 h, 155 μmol/liter). CSF neurotransmitter concentrations were normal, suggesting a peripheral deficiency. At 4 months of age, the BH4 was discontinued, no low Phe diet, and the Phe levels have remained normal. at 3.5 years, patient developing normally.

CaseNOTHPOs:

CasePreviousTesting: n/a

CaseGenotypingMethod: Direct nucleotide-sequence determination of PCR products from blood samples was performed for the coding exons (2-4) of PCBD1.

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

ClinVar ID: 16799

No star, one submission for OMIM

Homozygous

gnomAD: MAF (Euro-NF)= 2.2291E-4 (29/126606) hets only. No homozygotes recorded

AddCaseInfo: Family E in the article, and the proband had an older sibling that also carried the homozygous mutation in PCBD1, she was not noted as having increased Phe plasma levels, nor was ever treated with BH4 or low-Phe diet.

VariantEvidence: The mutant Q97X protein was expressed in E.Coli to determine the solubility of the mutant enzyme and the activity. The mQ97X fragment was mostly found in the insoluble fraction of the supernatant. The remaining fraction obtained in the soluble fraction did retain some activity in vitro. Interestingly, when more Q97X was obtained in the soluble fraction (by growing the E.coli at 20 degrees C), the Km (Michaelis constant) was 2-3 times higher than wildtype (text only, no figures to compare).

Patient part of the BIODEF database: PMID:8830181

Case# 16392, Spanish, 4yo report

Variant NM_000709.3(BCKDHA):c.659C>T (p.Ala220Val), NM_000709.3(BCKDHA):c.853G>C (p.Ala285Pro)

ClinVar 93367(c.659), 93375(c.853)

gnomAD c.659=0.00005805(East Asian), 0.000008156(Overall), c.853=0.00007896(European (Non-Finnish)), 0.00003970(Overall)

VariantEvidence 4% of normal BCKD activity in patient fibroblasts

CaseAddInfo in trans

CaseCI-1: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 365 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.194T>C (p.Ile65Thr)

ClinVar: 636 https://www.ncbi.nlm.nih.gov/clinvar/variation/636/

gnomAD: 0.0005574, https://gnomad.broadinstitute.org/variant/12-102894893-A-G?dataset=gnomad_r3

Variant2: NM_000277.3(PAH):c.261C>A (p.Ser87Arg)

ClinVar: 583 https://www.ncbi.nlm.nih.gov/clinvar/variation/583/

gnomAD: 0.00009294, https://gnomad.broadinstitute.org/variant/12-102894826-G-T?dataset=gnomad_r3

CaseDII-3: N/A

CasePresentingHPOs: N/A

HPOsFreeText: Pretreatment phenylalanine level at 725 umol/L

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: N/A

Variant1: NM_000277.3(PAH):c.561G>A (p.Trp187Ter)

ClinVar: 102736 https://www.ncbi.nlm.nih.gov/clinvar/variation/102736/

gnomAD: 0.00001760, https://gnomad.broadinstitute.org/variant/12-103249059-C-T

Variant2: NM_000277.3(PAH):c.782G>C (p.Arg261Pro)

ClinVar: 102832 https://www.ncbi.nlm.nih.gov/clinvar/variation/102832/

gnomAD: Not in gnomAD

each of these nucleotide positions is off by 36

so I came up with this:

NM_000159.3:c.387_388del(p.Glu129AspfsTer?)

register CAID

Mutalyzer

Case12 sex unknown, Spain

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

(Non-ambulatory, Nonverbal, Dystonia)

HPOsFreeText Clinical onset was "insidious," involving slowly progressive psychomotor delay, dystonic postures, lethargy, or macrocephaly. Phenotype was classified as "severe," with passive or static dystonia and an inability to stand up, walk, or speak. Diagnosed by routine GC-MS organic acid analysis in urine. There was high excretion of glutarate and 3-hydroxyglutarate with glutarate excretion being higher than that of 3-hydroxyglutarate.

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting GC-MS measured glutarate of 8188(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 3573(nv 2–14 mm/mol creatinine).

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 A293T variant, with the addition of a mismatch primer, destroys an HgaI restriction site. Thus, while the patient's DNA fragments would not cleave, control fragments would be cleaved. Likewise, the R402W variant destroys a MspI site. This would lead to uncleaved patient fragments and cleaved control fragments.

Variant 1. NM_000159.3(GCDH):c.877G>A (p.Ala293Thr), 2. NM_000159.3(GCDH):c.1204C>T (p.Arg402Trp), compound heterozygous

ClinVar 1. 2083, 2. 2085

gnomAD 1. MAF=0.0004013(African), no homozygotes, 2. MAF= 0.0007566(European(Finnish)), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case19 sex unknown, Spain

CasePresentingHPOs HP:0001332

(Dystonia)

HPOsFreeText Clinical onset was "insidious," involving slowly progressive psychomotor delay, dystonic postures, lethargy, or macrocephaly. Phenotypes were "mild," owing to static or improving dystonia, with maintained ability to walk without assistance. 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 HP:0002540

(Non-ambulatory)

NotHPOsFreeText n/a

CasePreviousTesting GC-MS measured glutarate of 8955(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 2262(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 R372K variant destroys an MnlI restriction site. Thus, while the patient's DNA fragments would not cleave, control fragments would be cleaved.

Variant 1. NM_000159.3(GCDH):c.1115G>A (p.Arg372Lys), 2. NM_000159.3(GCDH):c.1173delG (p.Asn392Metfs), compound heterozygous

ClinVar 1. 557606, 2. 370106

gnomAD 1. not in gnomAD, 2. MAF= 0.00005646(Latino), no homozygotes

CaseAddInfo n/a

CasePMIDs see note on previous studies

Case8 sex unknown, Spain

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

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

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

CaseNotHPOs n/a

NotHPOsFreeText n/a

CasePreviousTesting GC-MS measured glutarate of 1098(nv 2–10 mmol/mol creatinine) and 3-OH-glutarate 148(nv 2–14 mm/mol creatinine). In patient fibroblasts, %GCD activity was 6.

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 A293T variant, with the addition of a mismatch primer, destroys an HgaI restriction site. Thus, while the patient's DNA fragments would not cleave, control fragments would be cleaved.

Variant 1. NM_000159.3(GCDH):c.877G>A (p.Ala293Thr), 2. NM_000159.3(GCDH):c.268G>A (p.Glu90Lys), compound heterozygous

ClinVar 1. 2083, 2. 459949

gnomAD 1. MAF=0.0004013(African), no homozygotes, 2. MAF= 0.00008011(African), no homozygotes

CaseAddInfo n/a

CasePMIDs n/a

Case#: GA8, England, 15 years (onset), gender unknown.

CaseHPOs: HP:0000662, HP:0012026 (night blindness, (hyperornithinemia)

CaseHPOsFreeText: Presented with visual disturbances. Vitamin B6 responsive.

CaseNotHPOs: Neonatal encephalopathy

CasePreviousTesting: No previous DNA testing noted. Plasma ornithine at diagnosis 728 umol/L (normal <100)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Sequence analysis of the OAT gene from fibroblast or lymphocyte cDNA and genomic DNA. Variant: NM_000274.3(OAT):c.952G>A (p.Glu318Lys)

ClinVar: 56138

gnomAD: The maximum population minor allele frequency in gnomAD is 0.00002328 (European non-Finnish); no homozygotes in any population. VariantEvidence: When the variant was expressed in yeast, OAT enzymatic activity was <10% normal. This variant did not significantly affect protein levels but displayed a marked reduction of the hexamer (the active form) and an accumulation of the monomeric form.

Patient1: Male, 14 yo, Thai

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0001250, HP:0001876, HP:0002919, HP:0001942, HP:0001987, HP:0002187, HP:0002300, HP:0002540, HP:0006846, HP:0002901, HP:0001510 (poor feeding, lethargy, seizures, pancytopenia, ketonuria, metabolic acidosis, hyperammonemia, profound mental retardation, inability to speak, inability to walk, acute encephalopathy, hypocalcemia, growth delay)

HPOsFreeText: acute neonatal IVA, hemoglobin = 10g/dL, WBC = 3370/mm^3, platelets = 27,000/mm^3, bicarbonate = 10mmol/L, anion gap = 36mmol/L, low serum calcium, ammonia = 420µmol/L, treated with total blood exchange, treated with low-protein diet and leucine-free formula (150–250mg/kg per day of l‐glycine, and 100mg/kg per day of l‐carnitine), urine isovalerylglycine = 515

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: non-consanguineous family, symptom onset at 7 days old, diagnosed at 2wks old

CasePMIDs:

CasePreviousTesting: urine organic acid analysis with GC/MS (PMID: 27082169)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA extracted from peripheral blood, IVD coding exons and flanking introns amplified with PCR (primer in table 1), PCR products purified and sequenced with Big Dye Primer Cycle Sequencing Kit and ABI 210 Genetic Analyzer

Variant1: c.457–3_2CA>GG / no ClinVar or CAID

Variant2: NM_002225.3:c.1025A>G (p.Tyr342Cys) listed in paper as (p.Tyr371Cys)

CAID: CA7480839, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_002225.3%3Ac.1025A%3EG

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/15-40708332-A-G

Patient6: Female, 4yo

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 3.1 μmol l−1, IVG in urine mmol permol creatinine = 230, Ammonium (μmol l−1) = 56, pH = 7.37, Protein intake (g kg−1 per day) = 1.5, PDI/IQ in follow-up = 104

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_002225.3:c.158G>A listed in ClinVar as: NM_002225.4(IVD):c.149G>A (p.Arg50His)

CAID: CA7480513, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA7480513

ClinVar: 370843, https://www.ncbi.nlm.nih.gov/clinvar/variation/370843/

gnomAD: 0.00002784, http://gnomad.broadinstitute.org/variant/15-40699841-G-A

Variant2: NM_002225.3(IVD):c.941C>T (p.Ala314Val)

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

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

Case#: Patient 1, male, died on DOL 4, from the Faroe islands

CaseHPOs: HP:0003811 (neonatal death)

CaseHPOsFreeText: At 16 hours old, began grunting, was jittery, and had tachypnea. At 48 hours, had increased jitteriness, hypertonia, hypothermia, and alkalosis. Coma and death at 4 days. In urine, undetectable citrulline, argininosuccinate, and orotic acid. Plasma amino acids showed extremely elevated glutamine and alanine suggestive of hyperammonemia. No ammonia levels were available.

CaseNotHPOs: HP:0003218 (Orotic aciduria)

CasePreviousTesting: Analysis of urea cycle enzymes on post mortem liver tissue: CPSI activity was 30.7 U (normal >12), basal NAGS activity was 10 U (normal >34), arginine stimulated NAGS activity was 20 U (normal >144).

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Tissue or DNA from the deceased infant of family 1 was unavailable; blood genomic DNA from both parents to search for a mutation in the NAGS gene. All seven exons including intron/exon boundaries of the NAGS gene were amplified and sequenced.

Variant: NM_153006.2(NAGS):c.971G>A (p.Trp324Ter) (homozygous) (based on parental results; both parents are heterozygous)

ClinVar: 2428

gnomAD: Absent

VariantEvidence: NA

Case#: Pedigree 6 proband, Finland

CaseHPOs: HP:0012026 (hyperornithinemia)

CaseHPOsText: Patient noted to be "of historical interest" because he was the first patient in whom hyperornithinemia was recognized in gyrate atrophy (PMID 4122112). At age 8, choroidal degeneration ultimately diagnosed as gyrate atrophy, abnormal ERG; plasma ornithine concentration 10 times normal.

CaseGenotypingMethod: Variant identified by sequencing of genomic clones of OAT; sequencing of the remainder of the coding region and exon/intron boundaries was normal.

Variant: NM_000274.3(OAT):c.539G>C (p.Arg180Thr) (homozygous)

ClinVarID: 153

gnomAD: Maximum population minor allele frequency = 0.0007166 (Finnish); no homozygotes

VariantEvidence: When expressed in CHO-K1 cells, the variant results in no detectable OAT activity. Another Finnish patient (out of a group of 16) was also found to be homozygous for this variant.

CaseLE19: Male, 16 yrs report

CasePresentingHPOs: HP:0000964, HP:0002650, HP:0000501, HP:0000518, HP:0000750, HP:0010862, HP:0002572 (Eczema, Scoliosis, Glaucoma, Cataract, Delayed speech and language development, Delayed fine motor development, Episodic vomiting)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Variants not confirmed in-trans due to lack of parental testing

CasePreviousTesting: Specific plasma MMA levels, urine MMA levels, urine MA levels, and MMA/MA ratio available in Table 2; Congenital unilateral persistent hyperplastic primary vitreous (PHPV), causing glaucoma and cataract

CaseGenotypingMethod: See Group

Variant1: NM_001243279.3(ACSF3):c.1075G>A (p.Glu359Lys)

ClinVar: 31136, https://www.ncbi.nlm.nih.gov/clinvar/variation/31136/

gnomAD: 0.001054, https://gnomad.broadinstitute.org/variant/16-89180844-G-A

Variant2: NM_001243279.3:c.1239+2T>G

CAID: CA397142431, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA397142431

gnomAD: Not in gnomAD

Case# Case 1, F, Chinese, 4day old Age of Onset

CasePresentingHPOs HP:0011968, HP:0001276, HP:0002373, HP:0001954, HP:0008344

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

CaseMethod1 Whole Exome

CaseMethod2 Sanger

CaseGenotypingMethod validated whole exome findings with sanger and qPCR.

Variant NM_000056.4(BCKDHB):c.508C>T (p.Arg170Cys), NM_000056.3:c.659del

ClinVar 96590 (missense)

CAID CA658820635 (c.659del)

gnomAD 0.00001791 (European(Non-Finnish)), 0.000008123 (Overall)

CasePMIDs missense mentioned in 25381949

Case# Patient 17, Female, Turkish, 2mo diagnosis

CasePresentingHPOs HP:0004923

CasePreviousTesting screened for BH4 deficiency using dried blood and urine spots, Final di-agnosis was made by measurements of neurotransmitter and pterinmetabolites in cerebrospinal fluid (CSF) and urine, in addition toDHPR enzyme activity, which was assessed in whole red bloodcells

CaseMethod1 PCR

CaseMethod2 DGGE

Variant NM_000320.2:c.741A>T(p.R221Ter)

CAID CA658795309

VariantEvidence null

FamilyLabel Family 15

Family15PresentingHPOs HP:0001250

(Seizures)

HPOsFreeText seizure onset in neonatal period from minutes after birth until 3 weeks of age.

FamilyNotHPOs n/a

CountryOrigin Germany

Ethnicity n/a

Race Caucasian

Family15PreviousTesting Post treatment metabolic testing of plasma PA and AASA as well as urine AASA. Normal urine PA after pyridoxine treatment.

ProbandLabel Case 15

Case15previoustesting Pipecolic acid in plasma 7.0(nv 0.7-2.6µmol/liter), AASA in plasma 1.9(nv<0.2µmol/liter), urine AASA 16(nv<1mmol/molcreatinine).

Case15HPOsfreetext Probable PDE: either pyridoxine-responsive seizures and an affected sibling or neonatal seizures responsive to a single dose of pyridoxine with later recurrence of seizures again responsive to pyridoxine.

Case16

Case16previoustesting Pipecolic acid in plasma 9.1(nv 0.4-4.9µmol/liter), AASA in plasma 2.6(nv<0.2µmol/liter), urine AASA 10(nv<1mmol/molcreatinine).

Case16HPOsfreetext Definite PDE: formal pyridoxine withdrawal had resulted in reoccurrence of seizures that again responded to pyridoxine.

Variant NM_001182.4(ALDH7A1):c.1566-1G>T, homozygous

ClinVar 374140

gnomAD MAF= 0.00003529(European(non-Finnish)), no homozygotes

FamilyAddInfo n/a

FamilyPMIDs n/a

Patient10: Group 2

CasePresentingHPOs: same as group 2

CasePreviousTesting: same as group 2

CaseGenotypingMethod: same as group 2

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

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

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

Variant2: NM_002225.4:c.436A>G

CAID: CA391716744, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716744

**In ClinVar as: NM_002225.3(IVD):c.445A>G (p.Lys149Glu), https://www.ncbi.nlm.nih.gov/clinvar/variation/553403/

gnomAD: n/a

FamilyFSP470: France

FamilyPresentingHPOs: HP:0008969, HP:0002064, HP:0002460, HP:0003701, HP:0002395, HP:0007350, HP:0003487, HP:0031993 (Leg muscle stiffness, Spastic gait, Distal muscle weakness, Proximal muscle weakness, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Hoffman sign)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0006938, HP:0001317, HP:0002066, HP:0002464, HP:0100543, HP:0000973 (Impaired vibration sensation at ankles, Abnoral cerebellum morphology, Gait ataxia, Spastic dysarthria, Cognitive impairment, Cutis laxa)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: 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.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family displays autosomal dominant inheritance

Variant: NM_002860.4(ALDH18A1):c.755G>A (p.Arg252Gln)

ClinVar: 217117 https://www.ncbi.nlm.nih.gov/clinvar/variation/217117/

gnomAD: Not in gnomAD

Affected: 4

Unaffected: 5

Segregations: 4

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

FamilyFSP856: Portugal

FamilyPresentingHPOs: HP:0001270, HP:0001510, HP:0002317, HP:0002273, HP:0007350, HP:0003487, HP:0003487, HP:0000020, HP:0001249, HP:0002344, HP:0000252, HP:0003700 (Motor delay, Growth delay, Spastic gait, Tetraparesis, Lower limb hyperreflexia, Hyperreflexia in upper limbs, Babinski sign, Urinary incontinence, Intellectual disability, Progressive neurologic deterioration, Microcephaly, Generalized amyotrophy)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0002066, HP:0000973 (Gait ataxia, Cutis laxa)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: 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.

FamilyPreviousTesting: N/A

FamilyAddInfo: Family displays autosomal recessive inheritance, Family is compound heterozygous for these variants

Variant1: NM_002860.4(ALDH18A1):c.1910T>C (p.Leu637Pro)

ClinVar: 217120 https://www.ncbi.nlm.nih.gov/clinvar/variation/217120/

gnomAD: Not in gnomAD

Variant2: NM_002860.4(ALDH18A1):c.383G>A (p.Arg128His)

ClinVar: 217121 https://www.ncbi.nlm.nih.gov/clinvar/variation/217121/

gnomAD: 0.00006533, https://gnomad.broadinstitute.org/variant/10-97397114-C-T

Affected: 4

Unaffected: 13

Segregations: 11

AddSegregationInfo: Whole Exome Sequencing, Figure 1 Pedigree

CaseSE7: Female, Australia

CasePresentingHPOs: HP:0008353 (Neutral hyperaminoaciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseGenotypingMethod: Five loci were investigated for evidence of linkage to Hartnup due to their established role in amino acid transport including SLC3A2, SLC7A8, SLC1A5, SLC6A18, and SLC6A19. These 5 regions were studied with microsattelite markers and produced linkage only between D5S392 and D5S417, the region with SLC6A18 and 19. SLC6A18 did not increase neutral amino acid uptake in X. laevis oocytes so SLC6A19 was investigated and directly sequenced in the families each of which displayed a causal variant.

CasePreviousTesting: SLC1A5 had no causative variants detected.

CaseAddInfo: Asymptomatic except for hyperaminoaciduria

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?dataset=gnomad_r2_1

Variant2: NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)

ClinVar: 2020 https://www.ncbi.nlm.nih.gov/clinvar/variation/2020/

gnomAD: 0.0001960, https://gnomad.broadinstitute.org/variant/5-1213632-C-T

CaseWG2797: N/A

CasePresentingHPOs: HP:0012120 (Methylmalonic aciduria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband is asymptomatic and has an affected sibling with similar aciduria

CasePreviousTesting: Propionate Incorporation w/o hydroxycobalamin at 3.9 nmols/mg protein/18hr; Propionate Incorporation with hydroxycobalamin at 4.0 nmols/mg protein/18hr; Adenosylcobalamin synthesis percentage at 12.4%; Elevated methylmalonic values of 1400 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.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

CaseII-3: Female, Turkey

CasePresentingHPOs: HP:0001561, HP:0001789, HP:0000494, HP:0000463, HP:0005280, HP:0011829, HP:0000319, HP:0002705, HP:0002033, HP:0006829, (Polyhydramnios, Hydrops fetalis, Downslanted palpebral fissures, Anteverted nares, Depressed nasal bridge, Thin philtrum, Smooth philtrum, High narrow palate, Poor suck, Severe muscular hypotonia,

HPOsFreeText: Birth weight was 1890 g and length was 42 cm, Absent Moro reflex, Required ventilator support from birth

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Born with fractures of the left humerus and pes equinovarus

CasePreviousTesting: N/A

CaseGenotypingMethod: Whole blood smaples were obtained from the parents and the probands and DNA was extracted. WES was performed on II-2, with the results being sequenced and filtered for pathogenicity. Once the LMOD3 variant was detected, PCR amplification and Sanger sequencing was used to amplify exon 1 and confirm the results.

Variant: NM_198271.4:c.138dup (p.Ser47Glnfs*13)

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

PMID: 10915611

Gene: DBT

Disease: Maple syrup urine disease

MonDO: MONDO:0009563

InheritancePattern: AR

Case2: 8 days onset

CasePresentingHPOs:

HPOFreeText: Identified by after metabolic studies performed for evaluation of clinical disease.

CaseNotHPOs:

CasePreviousTesting: DBS C5 carnitine 0.97 umol/L (ref <0.46); plasma alloisoleucine 1.5 umol/L (ref <2.1); urine C5 carnitine 35.8, 80.6 umol/mmol creatine (ref <3.0); urine 2-EHA 116, 132 U (ref <5); urine 2-MBG 20.2, 36.7 (ref <2.3); urine 2-methylbutyric acid conjugates as R-isomer 45%, 43% (ref 43-56%).

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

Variant: NM_001609.3:c.908G>C (p.Gly303Ala) (homozygous)

CAID: CA378620840

gnomAD: European (non-Finnish) 0.00002323

VariantEvidence:

CaseAddInfo:

CasePMIDs:

Case3: 11 months onset

CasePresentingHPOs:

HPOFreeText: Identified by after metabolic studies performed for evaluation of clinical disease.

CaseNotHPOs:

CasePreviousTesting: DBS C5 carnitine 1.75 umol/L (ref <0.46); urine C5 carnitine 2.7 umol/mmol creatine (ref <3.0); urine 2-EHA 32, 8, 15 U (ref <5); urine 2-MBG 14.5 umol/mmol creatine (ref <2.3); urine 2-methylbutyric acid conjugates as R-isomer 46%, (ref 43-56%).

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

Variant: NM_001609.3:c.443C>T (p.Thr148Ile) (homozygous)

ClinVar: 9202

gnomAD: South Asian 0.002678

VariantEvidence: Decreases ACADSB enzymatic activity to 2.8% of wild type in vitro (PMID: 20547083).

CaseAddInfo:

CasePMIDs:

Case4: 6 years onset

CasePresentingHPOs:

HPOFreeText: Identified by after metabolic studies performed for evaluation of clinical disease.

CaseNotHPOs:

CasePreviousTesting: DBS C5 carnitine 0.5, 0.55 umol/L (ref <0.46); urine 2-EHA 152, 19, 43 U (ref <5).

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

Variant: NM_001609.3:c.1102T>C (p.Ser368Pro) (homozygous)

CAID: CA5730911

gnomAD: Ashkenazi Jewish 0.002200; Overall 0.0002488

VariantEvidence:

CaseAddInfo:

CasePMIDs:

Biallelic

Case#: Patient 8, female, 14 years (report)

CaseHPOs: HP:0003235, HP:0001249, HP:0001332 (Hypermethioninemia, Intellectual disability, dystonia)

CaseHPOsFreeText: demyelination

CasePreviousTesting: Plasma methionine 1114–1629; transamination products in plasma 41.2 uM (normal 0.2-0.54) and in urine 992 mmol/mol creatinine (normal 1.2-4.6), urine dimethylsuphide 535 nM (normal – trace-2 nM).

Variant: c.1043_1044delTG (homozygous)

ClinVar: NA

CAID: CA594460387

gnomAD: The highest population minor allele frequency in gnomAD is 0.000008791 (European non-Finnish); no homozygotes in any population

VariantEvidence: When the variant was expressed in bacteria, the amount and size of the protein was reduced on Western blot, and there was no detectable MAT1A activity.

CasePMIDs: 7573050 Points: 1 point. This individual is homozygous for a frameshift variant in MAT1A. When the variant was expressed in bacteria, there was no detectable MAT. The highest population minor allele frequency in gnomAD is 0.000008791 (European non-Finnish); no homozygotes in any population. The score is reduced because other causes of hypermethioninemia have not been ruled out.

Case1752 Caucasian

CasePresentingHPOs HP:0003571 (Propionicacidemia)

CaseNotHPOs n/a

CasePreviousTesting none reported

Variant 1. NM_000532.4(PCCB):c.1218_1231delGGGCATCATCCGGCinsTAGAGCACAGGA (p.Gly407Argfs), 2. NM_000532.4:c.1222del (p.Ile408SerfsTer?)

ClinVar 1.38875, 2. n/a

CAID 2. unregistered

gnomAD 1. not in gnomAD

CaseAddInfo parents NOT tested, phase unknown

CasePMIDs n/a

Case16 Female, Finland

CasePresentingHPOs HP:0003826, HP:0000202, HP:0000347, HP:0001162, HP:0001829, HP:0010066, HP:0000157, HP:0002101, HP:0000238, HP:0007370, HP:0010664, HP:0007260

(Stillbirth, Oral cleft, Micrognathia, Postaxial hand polydactyly, Foot polydactly, Duplicated hallux, Tongue abnormality, Defective lung lobation, Hydrocephalus, Callosal agenesis, Fused thalami, Type II lissencephaly)

HPOsFreeText Crown-heel body length 47cm, body weight 2520g, abnormal larynx/trachea, uterus duplex, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001627

(Congenital heart defect)

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 stillbirth, 34+0wk gestational age

CasePMIDs n/a

Case5: Female, 50 yrs report

CasePresentingHPOs: HP:0002355, HP:0100753, HP:0003089, HP:0003798, HP:0031237, HP:0031318 (Difficulty walking, Schizophrenia, Hamstring contracture, Nemaline bodies, Internally nucleated skeletal muscle fibers, Myofiber disarray)

HPOsFreeText: Jaw contractures, Pectoral contractures, Ankle dorsiflexor contractures, Quad contractures, Increased oxidative staining

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Daughter of Case 4, Sibling of Case 6

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case8: Female, 65 yrs report

CasePresentingHPOs: HP:0001263, HP:0030051, HP:0003326, HP:0003731, HP:0002540, HP:0003236, HP:0006466, HP:0005830, HP:0012785, HP:0009600, HP:0003798, HP:0031237, HP:0003555, HP:0001761 (Delayed milestones, Tip-toe gait, Myalgia, Quadriceps weakness, Non-ambulatory, Elevated serum creatine phosphokinase, Ankle contracture, Toe contractures, Flexion contracture of finger, Contracture of thumb, Nemaline bodies, Internally nucleated skeletal muscle fibers, Muscle fiber splitting, Pes cavus)

HPOsFreeText: Tendo-achilles release performed, NCPAP from 54 yrs, Jaw contractures, Nuclei clumps, Fiber type grouping, Required non-invasive nocturnal ventilatory support at age 54 years

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parental testing not performed

CasePreviousTesting: ACTA1 was sequenced and returned negative.

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case1: Female, 45 yrs report

CasePresentingHPOs: HP:0008994, HP:0002015, HP:0003236, HP:0003273, HP:0031237, HP:0003555, HP:0100295, HP:0012548 (Proximal muscle weakness in lower limbs, Dysphagia, Elevated serum creatine phosphokinase, Hip contracture, Internally nucleated skeletal muscle fibers, Fiber splitting, Muscle fiber atrophy, Skeletal muscle fatty infiltration)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Proband of Family 1, Mother of Case 2, Variant is de novo

CasePreviousTesting: N/A

CaseGenotypingMethod: The TPM2 gene was sequenced and variants identified. No other information is provided.

Variant: NM_003289.3:c.14_16delAGA (p.Lys7del)

ClinVar: 140486 https://www.ncbi.nlm.nih.gov/clinvar/variation/140486/

gnomAD: Not in gnomAD

Case#: 77 yo Female. French Canadian

Demographics: French-Canadian. Parents from an isolated island Quebec, Canada.

CasePresentingHPOs: HP:0033166, HP:0002090, HP:0200043, HP:0001875, HP:0032247, HP:0002205, HP:0006532,HP:0033005, HP:0040167, HP:0032215, HP:0003139, HP:0032155, HP:0002014, HP:0025085, HP:0001824, HP:0033431, HP:0032247, HP:0001875

CaseFreetextHPOs: Beginning at age 14 proband was hospitalized for pneumonia. Started at age 14- 62 developed pneumonia several times. Had immunoglobulin replacement therapy. Has finger and forehead warts. Multiple episodes of Bowen's Disease of cheek. Due to worsening CMV colitis she underwent total abdominal colectomy with end ileostomy at age 77.. CMV viral load was 8641 copies/mL. IgG 11.32(g/L), IgA .28(g/L), IgM.2 (g/L). IgA and IgM are below the reference range. Neutropenia occurred only while on (val)ganciclovir for CMV.

Person first evaluated at age 74. Colonic diseases No known consanguinity Proband was hospitalized as early as 14 years of age for pneumonia

CasePreviousTesting: Near-absence of ICOSL in plasma. Cell surface expression of ICOSL by flow cytometry-based evaluation of PBMC from whole blood revealed severely diminished levels on CD19+ B cells.

CaseMethod1: WES

CaseMethod2:

CaseGenotypingMethod: Whole exome sequencing (WES) was performed on whole blood DNA from the patient.

Variant: NM_015259.6:c.657C > G (p.N219K)

ClinVar: Not registered

CAID: CA321497070

gnomAD: 0.00006424

VariantEvidence: Proband was homozygous for the missense variant in ICOSLG, p.N219K. Similar to the previous paper this individual is also French Canadian. No known consanguinity. p.N219K variant is reported at the highest frequency of 0.00006424 (4/62262 non Finnish European alleles in gnomAD 2.1.1.

CaseAddInfo: Sibling of proband died of unknown cause or blood disorders

CasePMIDs:

Case#: 38 yo Male. Canadian

Demographics: French-Canadian. Parents from an isolated island Quebec, Canada.

CasePresentingHPOs: HP:0000246, HP:0032301, HP:0033004, HP:0002205, HP:0001875, HP:0004313, HP:0001888, HP:0000403, HP:0011108, HP:0012387, HP:0002090, HP:0200043, HP:0032215, HP:0032076, HP:0410028, HP:0100825, HP:0011107,

CasePresentingHPOsFreeText: Had recurrent sinusitis approximately once per year as a youth. Age 21 was hospitalized for pneumonia. Had genital warts at age 16. Absent cell-surface expression determines functional consequence of mutation on the T-cell. At age 35 IgG 10.9-17.6 (g/L), IgA .16-0.3(g/L), IgM 0.66-0.76 (g/L). IgA are below the reference range. At age 38 CD3+ T cells: 387; CD4+ T cells: 281 CD8+ T cells: 92 all below the reference range. Started intravenous immunoglobulin replacement which helped with his respiratory tract infection.

CaseNotHPOs HP:0002718, HP:0410295, HP:0410303, HP:0003453, HP:0031160, HP:0002863

CaseNotHPOsFreetext: Diphtheria

CasePreviousTesting: Flow cytometric analysis, using two different antibodies recognizing distinct epitopes of ICOSL, showed that its cell-surface expression was absent in P1. Confocal microscopy likewise demonstrated decreased cell-surface expression. Both showed that ICOSL was absent. Sequencing of CXCR4 identified no mutation.

CaseMethod1:WES

CaseMethod2:Sanger Sequencing

CaseGenotypingMethod: Whole-exome sequencing was performed on genomic DNA. Sanger Sequencing confirmed that he is homozygous for the variant.

Variant: NM_015259.6:c.657C>G(p.Asn219Lys)

ClinVar:

CAID: CA321497070

gnomAD: 0.00006424

​​VariantEvidence: No known direct consanguinity. RT PCR to compare the ICOSLG mRNA levels and it showed that there was not significant decay in the mRNA. We observed a similar phenomenon following transient transfection of HEK293T cells, which lack endogenous ICOSL, with either WT or p.N219K ICOSL protein. Western Blot analysis of whole cell lysates.p.N219K variant is reported at the highest frequency of 0.00006424 (4/62262 non Finnish European alleles in gnomAD 2.1.1.

CaseAddInfo: French ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. His parents were heterozygous and his healthy brother was homozygous for the WT allele

Case: Family 1 Moynihan Proband VII:7, female, Pakistani

CasePresentingHPOs: HP:0000407, HP:0004322, HP:0000135, HP:0100540, HP:0012385, HP:0002716, HP:0034920, HP:0034677, HP:0034391, HP:0030075, HP:0002862

CasePresentingHPOsFreeText: Eyelid swellings due to histiocytic deposits, diverse cytoplasmic inclusions in phagocytes and reticulum cells of bone marrow, Lymph node and eyelid show reactive features with small reactive lymphoid follicles and histiocytes within dilated sinuses resembling RDD. invasive ductal carcinoma grade 3 ER negative breast aged 43 years and carcinoma bladder (grade 3 papillary TCC) age 46 years

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of PRF1 and UNC5B

CaseGenotypingMethod: autozygosity mapping, genotyping (genome-wide linkage scan was performed using Affymetrix 250k SNP arrays), direct sequencing, PCR

Variant: c.300+1G>A homozygous

ClinVarID: or CAID: 130339/CA155238

gnomAD: This splice site variant in intron 2 is present in gnomAD v4.0.0 at a MAF=0.0002197 (20/91048 alleles) in the South Asian population with 0 homozygotes.

AddCaseInfo: brother is affected as well

PreviouslyPublished: PMID: 9545394

VariantEvidence: n/a

This variant is listed in table 1 and found on LitVar, but no case info is present and is likely mention of a previous publication

CaseP4 male, 45yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

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

HPOsFreeText Patient's sperm volume: 2.2mL(lower reference limit: 1.5), sperm concentration: 56million/mL(reference: 15), total motility after 1hr: 0%(reference: 40), vitality: 79%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 78%, abnormal head morphology: 58%, abnormal base: 14%, absent flagella: 50%, short flagella: 32%, coiled flagella: 34%, flagella of irregular caliber: 50%, multiple anomalies index: 3.4%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomaD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP3 male, 51yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

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

HPOsFreeText Patient's sperm volume: 1.7mL(lower reference limit: 1.5), sperm concentration: 56million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), vitality: 73%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 56%, abnormal head morphology: 20%, abnormal base: 32%, absent flagella: 22%, short flagella: 59%, coiled flagella: 27%, flagella of irregular caliber: 37%, multiple anomalies index: 2.7%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD not in gnomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

CaseP2 male, 54yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0012865, HP:0012868, HP:0003251

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

HPOsFreeText Patient's sperm volume: 1.8mL(lower reference limit: 1.5), sperm concentration: 6million/mL(reference: 15), total motility after 1hr: 1%(reference: 40), vitality: 80%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 56%, abnormal head morphology: 10%, abnormal base: 2%, absent flagella: 6%, short flagella: 32%, coiled flagella: 17%, flagella of irregular caliber: 68%, multiple anomalies index: 2.3%.

CaseNotHPOs n/a

CasePreviousTesting Previously screened all patients for DNAH1, CFAP43, and CFAP44 variants. Somatic karyotypes were normal.

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

gnomAD n/a

CaseAddInfo consanguinity

CasePMIDs 29449551

Case#: II-9, male, Asian, 38 yr, proband

DiseaseAssertion: HCM, LQT1

FamilyInfo: HCM passed on in family (figure 1)

CasePresentingHPOs: HP:0001279, HP:0001712, HP:0001639 (Syncope, Left ventricular hypertrophy, Hypertrophic cardiomyopathy)

CaseHPOFreeText: physical examination; 12-lead ECG (SR, HR 57 bpm, P 80 ms, PR 164 ms, QRS 102 ms, QTc 423 ms); 2D echocardiographic study with S5-1 probe (MLVWT 14 mm, EF 62%, LVMI 94.27 g/m^2);

CaseNotHPOs: HP:0030148 (Heart murmurs)

CaseNotHPOFreeText: No inverted T wave: Normal QTc 440 ms

CasePreviousTesting: Additional Sanger sequencing for KCNQ1, MKLY2, TMEM70

CaseGenotypingMethod: Illumina-SolexaHiSeq 2000 sequencing from peripheral blood leococytes; bi-directional Sanger sequencing;

Variant: absent

ClinVar: absent

CAID: CA389036862 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA389036862

gnomAD: absent

MultipleGeneVariants:

(1) KCNQ1 Variant:

Variant: NM_181798.1(KCNQ1):c.187C>T (p.Arg63Trp)

ClinVar: 53070 https://www.ncbi.nlm.nih.gov/clinvar/variation/53070/

CAID: n/a

gnomAD: absent

(2) MKLY2 Variant:

Variant: absent

ClinVar: absent

CAID: CA408526793 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA408526793

gnomAD: African 0.00006453 https://gnomad.broadinstitute.org/variant/20-30412153-A-G

(3) TMEM70 Variant:

Variant: NM_017866.6(TMEM70):c.440T>C (p.Ile147Thr)

ClinVar: 571761 https://www.ncbi.nlm.nih.gov/clinvar/variation/571761/

CAID: n/a

gnomAD: East Asian 0.0004893 https://gnomad.broadinstitute.org/variant/8-74893513-T-C

PMID: 32360764

Variant NM_000280.5:c.333C>A(p.Val111=)

Gene: PAX6

Disease: Ocular dysgenesis

InheritancePattern: AD

Notes Proband with confirmed aniridia and confirmed de novo appearance of the variant, summary in table 1, proband information in the "splice variant" section. It is noted however that the authors do not include the parental genotype or phenotype data.

Clinical Lab The Wessex Regional Genetics Laboratory has been contacted for variants c.333C>A and c.1183G>C, there is no additional information than what is in the table and if familial or de novo is claimed it is because parental samples were collected and tested negative for the variant in the published proband

Case#: Carelli proband, 20yo, Italian, male, onset in first year of life

DiseaseAssertion: Behr syndrome

FamilyInfo: Parents are unrelated. c.1705+1G>T was also identified in the affected mother and in nine maternal relatives, three of which (III-10, III-14 and III-18) are clinically unaffected (pedigree in Fig. 1A). The 43-year-old proband’s mother (Fig. 1A, III-4 in the pedigree) had isolated optic atrophy, most evident on the temporal side (Fig. 1C), which segregated as a dominant trait in her family (Fig. 1A). The other affected individuals in this family all suffered a non-syndromic optic atrophy, which started in childhood and progressively worsened, but remained as an isolated symptom. c.1146A>G (p.I382M) is present in the clinically unaffected father and sister. There were no MRI structural or metabolic abnormalities in the father (III-3) and the mother (III-4) of the proband, except for a few focal hyperintensities in the cerebral white matter (Fig. 1K–L). Neither signs of optic neuropathy nor abnormal nerve conduction velocities were recorded upon neuro-ophthalmological exam of the proband’s father and the elder sister (III-3 and IV-3).

CasePresentingHPOs: HP:0006934, HP:0000648, HP:0002066, HP:0002359, HP:0007663, HP:0002064, HP:0002403, HP:0001776, HP:0002395, HP:0003487, HP:0007078, HP:0012898, HP:0012897, HP:0003535, HP:0003387, HP:0001272, HP:0000543, HP:0010871, HP:0002313, HP:0001310, HP:0002075, HP:0000639

CaseHPOFreeText: Bilateral optic atrophy. Motor difficulties and visual acuity worsened during childhood. Nerve conduction studies showed delayed sensory-motor velocities with reduced amplitudes of motor potentials. Somatosensory evoked potentials could not be recorded and motor evoked potentials showed absent potentials at lower limbs and delayed latency at upper limbs. Brainstem evoked potentials were delayed bilaterally. Repeated urine organic acid gas chromatography/mass spectrometry analysis revealed mild elevation of 3-methylglutaconic acid (8–20 μmol/mmol creatinine). Sural nerve biopsy demonstrated a marked reduction of the large-diameter myelinated axons (Fig. 1E–G). Teased fibre analysis disclosed regions of demyelination confined to the paranodal region, clustered in some axons, suggesting secondary demyelination. Ultrastructural examination confirmed the reduction of myelinated axons (not shown). Elevated serum lactic acid after standardized exercise. mild cerebellar atrophy and pathological accumulation of lactate in the CSF of lateral ventriculi. OCT examination of retinal nerve fibre layer (RNFL) thickness shows a diffuse reduction of thickness compatible with the severe optic atrophy. Positive Holmes rebound phenomenon. Vision was light perception with severe nystagmus in any direction of gaze. Compared to controls, mitochondrial ATP synthesis driven by complex I substrates (pyruvate and malate) was incrementally reduced in the mother’s fibroblasts bearing the c.1705+1G>T (III:4) mutation and in the proband’s fibroblasts (IV:4) carrying both mutations.

CaseNotHPOs:

CaseNotHPOFreeText: cognitive delay

GenotypingMethod: Direct sequencing of the entire coding regions of the OPA1 gene and the flanking intronic boundaries. Sequence analysis of the OPA3 gene excluded the presence of pathogenic mutations.

PreviouslyPublished:

Variant: c.1705+1G>T; c.1146A>G (p.I382M)

CAID: CA10576007

SupplementalData:

Case#: Case 12DG1568, female, Arab, 18mo

DiseaseAssertion: MPS Ih

FamilyInfo: Parents are a second-degree consanguineous couple with three other healthy children, and they had a son who died at 12 years of age and a cousin with a similar phenotype

CasePresentingHPOs: HP:0000280, HP:0100876, HP:0005280, HP:0000463, HP:0000256, HP:0001433

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: NM_000203.5(IDUA):c.613_617dup (p.Glu207fs) homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: genotype and phenotype in Table S1, S6

CaseVII-3: Male, 4 years report, Turkey

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

HPOsFreeText: -3.44 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, Mutation is at splice donor site at Intron 2

CasePreviousTesting: Calcium levels (9.0 mg/dL), Decreased serum phosphate levels (3.1 mg/dL; reference 3.8-6.5), Elevated serum ALP (393 IU/L; reference 90-325), 25OHD3 levels (4.9 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (154.7 ng/L), TPR levels (58.7), Decreased TmP/GFR levels (1.82; 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(PHEX):c.187+1G>T

CinVar: 438537 https://www.ncbi.nlm.nih.gov/clinvar/variation/438537/

gnomAD: Not in gnomAD

CaseII:II-2: Female, 37 years, Turkey

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

HPOsFreeText: -3.95 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 novel, Mother of II:II-3

CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.1 mg/dL; reference 2.7-4.5), Normal serum ALP (111 IU/L; reference 41-120), 25OHD3 levels (10.5 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (73 ng/L), TPR levels (87), Decreased TmP/GFR levels (1.70; reference 2.2-3.6)

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.979_983dup (p.His329Thrfs*4)

CAID: CA913187410 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913187410

gnomAD: Not in gnomAD

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Notes: The proband reported has clinical features of neurofibromatosis, with a de novo donor splice site variant in NF1, as well as a 12-bp deletion in RAB39B, which the authors assert was responsible for the phenotypes of severe ID, behavioral problems and aggressiveness.

This variant was mentioned only because a novel variant was found at the same amino acid. No new case or experimental info.

CaseID D

VariantInPub IVS2+9G>A

MANE NM_001368894.2:c.-129+9G>A

Zygosity heterozygous

PhenotypesProband HP:0000568, HP:0000482, HP:0000518, HP:0000639, HP:0000647, HP:0000491

FamilyInfo No family or segregation information was included

SpliceFormVariant No RT-PCR or northern blot to confirm the intronic substitution lead to a splice variant

Case#: Ma_Proband

Demographics: east Asian? referenced in passing in discussion section

CasePresentingHPOs: HP:0003182, HP:0008812, HP:0002655, HP:0003621, HP:0000943, HP:0001498, HP:0003049, HP:0002857, HP:0004689,

CaseNotHPOs: HP:0008445, HP:0002751, HP:0000768, HP:0008445

CasePreviousTesting: Previous diagnosis Developmental dysplasia of the hip (DDH)

CaseMethod1: quantify urinary excretion of glycosaminoglycans using dimethylmethylene blue

CaseMethod2:

CaseGenotypingMethod: Whole exome sequencing

Variant HGVS: 1) NM_000512.5:c.1156C>T 2) NM_000512.5:c.1288C>G

ClinVar: 1) 700 2) N/A

CAID: 1) CA221040 2) CA397096290

gnomAD v2: 1) 16-88891261-G-A 2) N/A

VariantEvidence:

CaseAddInfo: Onset of symptoms age 8, compound het

CasePMIDs:

Family#PresentingHPOs: None

FamilyNotHPOs: Free of clinical phenotypes

CountryOrigin: China

Ethnicity: Chinese

Race: east Asian

Family#GenotypingMethod: Whole exome sequencing

Affected: None reported

Unaffected: mother and maternal grandmother carriers of same allele, father carrier for separate allele

Segregations: 2?

PublishedLOD: N/A

eLOD: too few segregations

AddSegregationInfo:

ProbandLabel: Ma_Proband

Variant: Maternal - NM_000512.5:c.1288C>G Paternal - NM_000512.5:c.1156C>T

ClinVar:

CAID:

gnomAD:

FamilyAddInfo: paternal allele is previously reported as pathogenic, maternal allele and has only been reported in one proband/family

FamilyPMIDs: 34557487

CA3281798

Variant 1: CA8401572 Variant 2: ClinVar ID: 66035

Case#: Consequence 23 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.2788G>A (p.Glu930Lys)

ClinVar: 42933 https://www.ncbi.nlm.nih.gov/clinvar/variation/42933/

CAID: n/a

gnomAD: absent

Case#: Consequence 20 Table 1 in Data Supplement (3 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.4066G>A (p.Glu1356Lys)

ClinVar: 164294 https://www.ncbi.nlm.nih.gov/clinvar/variation/164294/

CAID: n/a

gnomAD: absent

Case#: Consequence 9 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.427C>T (p.Arg143Trp)

ClinVar: 164401 https://www.ncbi.nlm.nih.gov/clinvar/variation/164401/

CAID: n/a

gnomAD: 0.0001087 East Asian https://gnomad.broadinstitute.org/variant/14-23901923-G-A

Case#: Consequence 30 Table 1 in Data Supplement (2 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.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: Lin Patient-female, south Asian, 5 years old at diagnosis

CasePresentingHPOs: HP:0001945, HP:0002013, HP:0002027, HP:0002240

CasePresentingHPOsFreeText: Mildly elevated liver function tests (AST 48 U/L, ALT 80 U/L) upon initial visit, transaminases (AST 133 U/L, ALT 112 U/L) remained elevated after a month. Non-fasting lipid levels were abnormal; repeat testing showed a fasting total cholesterol of 305 mg/dL and a triglyceride level of 142 mg/dL. Diffuse, microvesicular steatosis in the hepatic parenchyma. Portal tracts were expanded by foamy macrophages containing finely vacuolated material, which was periodic acid-Schiff positive and resistant to diastase digestion. Trichrome stain for collagen showed mild portal fibrosis with early delicate bridging fibrosis. Ultrastructurally, the cytoplasm had a moth-eaten appearance with the presence of lipid droplets and cholesterol crystals. Low acid lipase activity of 7.2 (no units provided) in the liver, with follow up low level of lysosomal acid lipase activity (0.008 nmol/punch/h) in blood.

CaseNOTHPOs: HP:0032316, HP:0001744, HP:0001404, HP:0001396, HP:0001408

CaseNOTHPOSFreeText:

CasePreviousTesting: Abdominal ultrasound. Infection workup was negative for cytomegalovirus, hepatitis A, Lyme disease, and malaria. She did have a positive Epstein-Barr virus IgM. CT of the abdomen and pelvis revealed an enlarged liver measuring up to 17cm in width and craniocaudal dimension. Test results for autoimmune hepatitis, WD, and alpha-1-antitrypsin deficiency were negative. Liver biopsy.

CaseGenotypingMethod: LAL gene sequence analysis was performed.

Variant: c.57_60delTGAG and c.894G>A

ClinVarID: or CAID: CA2573331826 and 203361

gnomAD: This proband has a four-nucleotide deletion, c.57_60delTGAG, in exon 2 of the LIPA gene. This variant is predicted to result in a premature translation stop downstream of the deletion (p.Glu20GlyfsTer6). The variant is not present in gnomAD. This proband is scored default points.

This proband has a synonymous variant, Gln298= on exon 8/10 in a cononical splice site, which causes an abnormal splicing that results in the in-frame skipping of exon 8. The variant is reported in 167/128942 European (non-Finnish) alleles at a frequency of 0.001295, with no homozygotes in gnomAD v2.1.1. This is the most frequent variant in CESD patients (present in 40-60% of patients reported in the literature), but it is not confirmed if this is due to a hotspot or a common ancestor. This proband is scored default points.

AddCaseInfo: Confirmed in trans

PreviouslyPublished: no

VariantEvidence: Predicted evidence only for deletion variant.

Expression analysis in patient fibroblasts found lysosomal acidic lipase (LAL) activity to be reduced to 6-12% of wild type (PMID: 22227072).

Case# Zhong 3:2, Male, China

CasePresentingHPOs (HP:0007675, HP:0000580, HP:0007994, HP:0100019) no?

CasePreviousTesting no

CaseMethod1 WES

CaseMethod2 Sanger

Variant NM_004698.2:c.1532A>C

CAID CA342282924

Case#: V:3

Demographics: Pakistani

CasePresentingHPOs: HP:0004322, HP:0000768, HP:0000470, HP:0002857, HP:0002650, HP:0002007, HP:0000431, HP:0010674, HP:0002515, HP:0009803, HP:0006119, HP:0001216, HP:0002986, HP:0003027, HP:0008802, HP:0030299, HP:0000926, HP:0004568

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Proband whole exome seq

Variant: NM_000512.5:c.697G>A

ClinVar: 1048200

CAID: CA8235027

gnomAD: 16-88902194-C-T

VariantEvidence: previous pub as pathogenic, and in silico data suggesting damage to catalytic domain

CaseAddInfo: Family was tested via single gene sanger seq., consanguineous parents both carriers, two affected siblings and three unaffected siblings

CasePMIDs:

Case# F3-II2, female, 1yo onset, French

CasePresentingHPOs HP:0006579, HP:0003155, HP:0001290, HP:0001397, HP:0001395, HP:0001263, HP:0001250, HP:0000718, HP:0000713, HP:0000709, HP:0012347, HP:0003124, HP:0003141, HP:0010837 (Neonatal Jaundice, Elevated alkaline phosphatase, Hypotonia, Steatosis, Hepatic fibrosis, Psychomotor delay, Seizures, Aggressive behavior, Agitation, Psychosis, Abnormal protein N-linked glycosylation, High cholesterol, Increased LDL cholesterol, Low ceruloplasmin)

HPOsFreeText Persistent moderate hypotonia, elevated AT, necrotic lesions on liver biopsy, steatosis and fibrosis(1yo), developed various behavioral issues by age 25

CaseNotHPOs n/a

CasePreviousTesting Metabolic work up: AST 1,780 U/l[normal range, 0–50 U/l], ALT 390 U/l[normal range, 0–50 U/l], and ALP 950 U/l [normal range, < 360 U/l], with increased bone fraction, ceruloplasmin 10 mg/dl[normal range, 15–60 mg/dl], type 2 CDG, abnormal N-glycosylation

CaseMethod1 Sanger

CaseMethod2 n/a

CaseGenotypingMethod Sanger on proband targeting CCDC115.

Variant NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser), homozygous

ClinVar 218967

gnomAD 0.00002384(European (Non-Finnish)), 0.00001086(Total)-3 heterozygotes

VariantEvidence n/a

CaseAddInfo unaffected brother

CasePMIDs 29759592

Case# F2-II1, male, Italian, 2yo diagnosis

CasePresentingHPOs HP:0006579, HP:0001433, HP:0010837, HP:0003124, HP:0003155, HP:0001263, HP:0001999, HP:0025321, HP:0012358, HP:0012347, HP:0003141 (Neonatal jaundice, Hepatosplenomegaly, Decreased ceruloplasmin, High cholesterol, Elevated alkaline phosphatase, Psychomotor delay, Dysmorphic facies, Liver copper accumulation, Abnormal protein O-linked glycosylation, Abnormal protein N-linked glycosylation, Increased LDL cholesterol)

HPOsFreeText Elevated AT, ALT, cholesterol, jaundice, hepatosplenomegaly, low blood ceruloplasmin(neonate), Mild psychomotor disability, mild dysmorphic facies (2yo)

CaseNotHPOs n/a

CasePreviousTesting Failed to detect ATP7B on suspected Wilson disease. Metabolic work up: AST 422 U/l[normal range, 0–50 U/l], ALT 588 U/l[normal range, 0–50 U/l], ALP 976 U/l[normal range, < 360 U/l], type 2 CDG (2yo). Hepatic copper 125 μg/g dry weightnormal range, <40 μg/g, Altered ApoC3 pattern, type 2 CDG pattern