Case#: Family V, Patient 9, female, 1yo at diagnosis, 5yo at death, Tunisia (Mahdia), black

DiseaseAssertion: MPS1, Hurler

FamilyInfo: Parental consanguinity (first cousins). Age of parents at proband's birth: 50 years (M) 62 years (F). 6 unaffected siblings

CasePresentingHPOs: HP:0010864, HP:0004322, HP:0001537, HP:0000692, HP:0006482, HP:0030812, HP:0001999, HP:0007957, HP:0000943

CaseHPOFreeText: Height=102cm (-3DS). Weight=18kg (-1 DS). IDUA activity in leukocytes=0,020 μKat/kg (Normal values 1.7-3.5 μKat/kg of protein).

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: Direct sequencing of PCR products from each of 14 exons and flanking intron-exon junctions

PreviouslyPublished: n/a

Variant: p.R628X homozygous. Proband also had the following polymorphisms: A8A, A20A, H33Q, R105Q, A314A, N181N, T410T, V554I, IVS6+21c>a, IVS7+79c>t, IVS7-45g>c, IVS9+36t>c, IVS10+140c>a, IVS11+33c>t, IVS12+13c>t, IVS12-31c>g

ClinVar: 550421

CAID: CA2802462

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

SupplementalData: n/a

Variant NM_001198868.1(CAPN1):c.1579C>T (p.Gln527Ter)

ClinVar 225766

PMID:

Gene: OPA1

Disease: hereditary optic neuropathy

980 patients in this study with suspected hereditary optic neuropathies were evaluated by searching for the ten primary LHON-causing mtDNA mutations and examining the entire coding sequences of the OPA1 and OPA3 genes. 295 had variants in OPA1; however the exact count for this variant was not provided and neither was any additional phenotypic information.

Case II-6: 56, Female

CasePresentingHPOs: hypertension, proximal weakness, with occasional cramping in both of her lower limbs, voice sounded particularly nasal, mild scapular winging, slight muscular atrophy on temporal, deltoids and thigh muscle extensors, mild lordosis

CasePresentingHPOsFreeText: Pain, temperature, vibration and proprioception were preserved as well as her coordination. myopathic pattern with reduced duration and amplitude of motor unit action potentials (MUAPs) specifically on thigh extensors

CaseNOTHPOS: dysphagia or dysphonia

CaseNOTHPOSFreeText: did not find paraspinal complex repetitive discharges, did not find any alteration on the tissue specimen analysis using hematoxylin and eosin

Variant: reduction in alpha-glucosidase activity (Neutral/acid: 61.0, reference: <30) and her GAA gene sequencing showed the two same pathologic heterozygous compound mutations found on our first subject (II-8) (c.-32-13T>G (rs386834236, intronic) and c.2560C>T (rs121907943, p.Arg854Ter))

*she did not have the third variant found on subject II-8 (c.1551+42G>A (rs115427918, intronic))

PMID: 25252036

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 34387910

Gene: GALNS

Disease: Mucopolysaccharidosis IVA "Morquio A syndrome"

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Review

Variants 1. NM_000512.5:c.1156C>T 2. NM_000512.5:c.901G>T 3. NM_000512.5:c.337A>T 4. NM_000512.5:c.346G>A 5. NM_000512.5:c.120+1G>A[‐] 6. NM_000512.5:c.860C>T 7. NM_000512.5:c.1171A>G 8. NM_000512.5:c.953T>G 9. NM_000512.5:c.1023C>G 10. NM_000512.5:c.415G>A

Case# III-1, Female, Caucasian

CasePresentingHPOs HP:0001643

CaseMethod1 WES

CaseMethod2 PCR

Variant NM_001136239.3(PRDM6):c.788G>C (p.Cys263Ser)

ClinVar 243050

VariantEvidence Functional in vitro characterization of PRDM6 p.Cys263Ser in HEK293 cells and human aortic VSMCs showed that the variant protein significantly loses its capability for nuclear localization (Fig 3). DNA overexpression in adenovirus virus infected WT and mutant variants showed MYH11 is also not suppressed by mutant where it is suppressed in WT (Figure 4). Immunoblots of histones in WT human aortic smooth muscle transfected with the variant showed reduced histone modification and and suppression of contractile proteins. (Fig. 5)

Case# B1-3, Male, UK

CasePresentingHPOs HP:0001279

CasePreviousTesting re-sequenicing of genome

CaseGenotypingMethod genotyped for five microsatellite markers spanning TMEM43 on chromosome 3p25

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link

Case: Alonso-Perez_Patient 2, Female, 41yo, Spanish

DiseaseAssertion: Sandhoff Disease

CasePresentingHPOs: HP:0000007, HP:0001260

CaseHPOFreeText:

CaseNOTHPOs: HP:0002380, HP:0001324, HP:0003202

CaseNOTHPOFreeText: No signs of cerebellar or sensory dysfunction, deep tendon reflexes were normal

CasePreviousTesting: Nerve conduction studies and EMG were performed with normal results. Serum CK levels were tested and found to be elevated with the rest of the biochemical analysis normal. MRI was normal with no involvement of the brain. Serum β-hexosaminidase-enzyme activity assay showed low levels.

GenotypingMethod: Sanger sequencing of SMN1, DYNC1H1 and BICD2 genes showed no pathogenic variants. WES revealed HEXB mutations.

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: NM_000521.4, c.171delG (p.Trp57Cysfs7)

CAID: CA3305751

gnomAD: MAF: unavailable in gnomAD, gnomAD variant ID: 5-73981254-TG-T

VariantEvidence: This variant is known to be pathogenic and was previously published only in infantile cases of SD, PMID: 22789865. Total hexosaminidase activity in fibroblasts from the patients with this variant in that paper range from 2.3-9.5% of the normal control levels.

MultipleGeneVariants AR, allele on second allele

Variant: c.1510C>T (p.Pro504Ser)

CAID: CA116493

gnomAD: MAF: 0.0002259, Latino/admixed American, gnomad variant ID: 5-74016469-C-T

VariantEvidence: This variant is known to be pathogenic and was previously published in adult cases of SD, PMID: 9694901. This study concluded the effect of the mutation on ganglioside hydrolysis, combined with its effect on intracellular transport, produces chronic Sandhoff disease.

PMID: 17417613

Gene: PAX6

Variant c.-129+9G>A and c.136C>G

Disease: Ocular dysgenesis

MonDO: MONDO:0700246

InheritancePattern: AD

Notes p.Leu46Pro had microphthalmia, cataracts and nystagmus

Case# Postma 3:1, male, 10yo, white

CasePresentingHPOs HP:0004758, HP:0000980, HP:0005184, HP:0000961, HP:0002789

CasePreviousTesting no

CaseMethod1 PCR

CaseGenotypingMethod amplified/screen of CASQ2, SCN5A, HRC, PLN, RYR2, KCNQ1, KCNH2, and KCNK1 genes

Variant NM_001232.3:c.532+1G>A

CAID CA341763774 link

VariantEvidence not in this article

Case12 Male, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001841, HP:0010066, HP:0001627, HP:0000157, HP:0002101, HP:0002323, HP:0000316, HP:0000445, HP:0001162, HP:0030449

(Oral Cleft, Micrognathia, Preaxial foot polydactyly, Duplicated hallux, Congenital heart defect, Tongue abnormality, Defective lung lobation, Anencephaly, Hypertelorism, Broad nose, Postaxial hand polydactyly, Therapeutic abortion)

HPOsFreeText Crown-heel length 19.5cm, body weight 245g, abnormal larynx trachea, uterus duplex, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus, gliovascular tissue on the base of the cranium, hypertelorism, broad nose, postaxial polydactyly in hands, and preaxial polydactyly in feet

CaseNotHPOs HP:0001161

(Hand polydactyly)

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 induced abortion at 24+0wk gestational age

CasePMIDs n/a

Case#: Family AU-1, 35yo, female, Austrian

DiseaseAssertion: DOA+

FamilyInfo: positive family history, 2 relatives in table 1

CasePresentingHPOs: HP:0000648, HP:0000365, HP:0001251, HP:0000590, HP:0001138

CaseHPOFreeText:

CaseNotHPOs: HP:0003198

CaseNotHPOFreeText:

PreviouslyPublished: n/a

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

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

ClinVar: 30461

CAID: CA10575554

SupplementalData:

This case has been added to the VCI and assessed already.

PreviouslyPublished: PMID: 18158317

PMID: 35859948

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case Report

PatientCell CL:0000057 (Fibroblast)

GeneFunction GO:0032006, (regulation of TOR signaling)

GeneAlteration n/a

FunctionalEvidence Western blot of PS6 isoforms, a product of mTOR signalling, were 74% reduced in patient 2-1 fibroblasts compared to control (Fig 3).

Western blot of PS6 in subject 1-1&1-2 fibroblasts also demonstrated 78% reduced PS6 compared to controls (Fig 2b).

As S6 is phosphorylated during normal mTOR activation, reduced PS6 suggests reduced mTOR signalling.

29283439 (fig 3) suggests that the p.Arg126Ter variant in patient fibroblasts causes increased autophagy compared to controls due to the increase in autophagiosomes. (fig 5) the same variant also leads to excess oligosaccharides as a downstream effect of increased autophagy as show using mass spec.

FAVariants (Fig 3) NM_001163435.2(TBCK):c.831_832insTA (p.Pro278Tyrfs), ClinVar: 225238, (Fig 2) NM_033115.4(TBCK):c.1708+1G>A, ClinVar: 183338

Case#: He_12

CasePresentingHPOs: skeletal deformities: HP:0000924, HP:0012069, reduced GALNS activity in leukocytes (0.8 pmol/g protein/17hr)

CaseGenotypingMethod: Sanger of GALNS exons

Variant: p.R386C & p.W403_T404delinsCS

ClinVar: 700 & 1048331

CAID: CA221040 & CA916079760

gnomAD: 16-88891261-G-A & n/a

Case#: He_21

CasePresentingHPOs: HP:0000924, HP:0012069, GALNS activity in leukocytes 0 pmol/g protein/17hr

CaseGenotypingMethod: Sanger of PCR amplified GALNS exons 1-14

Variant: p.W520X & p.G290R

ClinVar: 1048427 & 93171

CAID: CA397076034 & CA221049

gnomAD: n/a & 16-88880857-C-T

PMID: 24035930

Gene: GALNS

Disease: Mucopolysaccharidosis type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

PMID: 23698346

Gene: ARHGEF18

Disease: Retinitis pigmentosa

MonDO: MONDO:0019200

Family#: Family IV

PresentingHPOs: HP:0003563 (decreased LDL cholesterol)

PresentingHPOsFreeText: FHBL diagnosis was based on low levels of fasting calculated plasma LDL-C < 50 mg/dL without lipid lowering therapy. Affected relatives were diagnosed by LDL-C < 80 mg/dL and/or ApoB <50 mg/dL.

FamilyMethod1: Next generation sequencing

FamilyGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

ProbandLabel: Family IV-I:1

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter)

CAID: CA345983128

gnomAD: Absent

Case#: Family 1- II:2, female, 49 years

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0001397, HP:0000819 (liver steatosis, diabetes)

CasePreviousTesting: TC 143 mg/dl, LDL-C 20 mg/dl, HDL-C 120 mg/dl, TG 18 mg/dl (see additional values in Table 1). ApoB100 <10 mg/dl (normal range 49-88) (Supplemental data) Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter), heterozygous

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

Family#: Family M

PresentingHPOs: HP:0003563 (decreased LDL cholesterol concentration)

PresentingHPOsFreeText: <5th percentile for LDL cholesterol

CountryOrigin: United States

Ethnicity: Caucasian

Race:

Family#PreviousTesting: No other genetic testing performed.

Family#Method1: PCR

Family#Method2: Sanger sequencing

Family#GenotypingMethod: PCR amplification of the entire APOB coding region, exon/intron junctions, 5' upstream, 5' and 3' untranslated regions, followed by cloning and sequencing in proband. Slot blot analysis of genomic DNA from family members.

AddSegregationInfo: Father (43 yo) and two sibs of the proband are heterozygous for an APOB variant and have <5th percentile LDL-cholesterol (47 mg/dl, 29 md/dl, and 16 mg/dl respectively)) based on https://www.ncbi.nlm.nih.gov/books/NBK351/ (Table 31.9); LDL-cholesterol level was no available for the mother but she is heterozygous for an APOB variant; two affected sibs have 0 LDL-cholesterol and are compound heterozygous.

ProbandLabel: CM (II:3)

Variant: Compound heterozygous: Variant 1: NM_000384.2:c.537+1G>T (paternal) Variant 2: NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

ClinVar: N/A

CAID: Variant 1: CA345962364 ; Variant 2: CA052017

gnomAD: Variant 1: Not in gnomAD; Variant 2: 0.00002640 (Euro non-Finnish)

FamilyAddInfo: Inheritance pattern is consistent with semi-dominant, in that father and both heterozygous sibs have low levels of LDL-cholesterol (levels not available for mother), which rules out abetalipoproteinemia (in which heterozygotes have normal LDL-cholesterol levels).

Case#: 7, female, 2 y 5 m (current), Chinese

CasePresentingHPOs: HP: 0008344, HP: 0012751, HP: 0012696 (elevated A keto acids in urine, abnormal signals in cerbral ganglia, abnormal thalamic MRI signal intensity)

HPOsFreeText: leucin: 621.72 uM, valine: 594.15 uM, isoleucine: 225.21 uM, Alloisoleucine: 76.62 uM

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: detected by newborn screening, 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.482T>G (p.Val161Gly), NM_183050.3:c.508C>T (p.Arg170Cys)

ClinVar: not found, 96590

CAID: CA364657700, CA224301

gnomAD: not found, 0.00001759 (European, non-Finnish)

CaseII-3: Female, 2 years, Turkey

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

HPOsFreeText: -2.09 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, Daughter of II:II-2

CasePreviousTesting: Calcium levels (10.2 mg/dL), Decreased serum phosphate levels (2.1 mg/dL; reference 3.8-6.5), Elevated serum ALP (531 IU/L; reference 90-325), 25OHD3 levels (31.1 ng/ml), PTH levels (52.5 ng/L), TPR levels (62.3), Decreased TmP/GFR levels (1.31; 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.979_983dup (p.His329Thrfs*4)

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

gnomAD: Not in gnomAD

Case#: Lesage_Proband

Demographics: Male, 39y at report, France

CasePresentingHPOs: HP:0001300, HP:0002322, HP:0001256, HP:0100660, HP:0002451, HP:0100710,

Proband was diagnosed with early-onset Parkinsonism. Proband had asymmetric rest tremor, akineto-rigid syndrome, and showed good response to Levodopa and normal brain MRI. He required sheltered employment due to intellectual disability. 8y after disease onset, patient developed treatment-related complications including motor fluctuations. Proband showed good global cognitive performance but difficulty concentrating and subcortico-frontal signs. Psychiatric interview revealed dysthymic disorder. Proband died at 55y, after apomorphine treatment was initiated.

CaseNotHPOs: No pyramidal, cerebellar, or ocular disorders

CasePreviousTesting: Exome analysis in the patient excluded variants in all other known PD genes.

CaseMethod1: WES

CaseMethod2:

CaseGenotypingMethod: The variant was identified by data mining exomes for coding and splice site variants in RAB39B.

Variant: NM_171998.4:c.557G>A (p.Trp186Ter)

ClinVar:

CAID: CA414923761

gnomAD:

VariantEvidence: The proband was hemizygous for the null variant, Trp186Ter in exon 2/2. NMD is not predicted. The evidence is scored reduced points. (0.5)

CaseAddInfo: No family history of PD is reported.

CasePMIDs:

annotating here since this is a PDF

Case#: Yamagishi Case 5, female, 1y at clinical dx, 20y at enzymatic dx, 31y at death

DiseaseAssertion: Hurler/Scheie

FamilyInfo: n/a

CasePresentingHPOs: HP:0002240

CaseHPOFreeText: height=117cm at 21yo. cardiac involvement. CHF caused death

CaseNotHPOs:

CaseNotHPOFreeText: mental delay

PreviouslyPublished: n/a

Variant: 704ins5; R89Q

ClinVar: 11921; 11922

CAID: CA256123; CA256124

SupplementalData: n/a

PMID 21436073

Diesease Bone marrow failure linked to pulmonary fibrosis

Case# SAL-399-073, Female, 46yo, French, Hispanic

CasePresentingHPOs HP:0002385, HP:0011448, HP:0001260, HP:0002066, HP:0002015, HP:0002650, HP:0001272

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.463C>T(p.Q155X), NM_005186.3:c.1142C>T(p.R512C)

CAID CA381242841, CA381248914

gnomAD 0.00003567

VariantEvidence nonsense, missense in trans with null variant

CaseAddInfo in article supplement

Case 4: HP:0001639, NM_005655.3:c.610G>A (p. Ala204Thr), gnomAD= 2.03e-5, Other= 1.823e-4

This variant is mentioned as a reference to a previous publication (PMID: 25146916) which has already been included in the VCI.

Proband 2: male, Dx at 41 years, LV septal wall thickness = 22mm, improved following transseptal alcohol ablation, 3 unaffected children

HP:0001639, HP:0011103

Hypertrophic cardiomyopathy, Abnormality of the left ventricular outflow tract

Variant: NM_145046.4(CALR3):c.245A>G (p.Lys82Arg)

ClinVar ID: 30907

https://www.ncbi.nlm.nih.gov/clinvar/variation/30907/

ExAC Score: Overall 0.0005987

http://gnomad.broadinstitute.org/variant/19-16601330-T-C

Model: Zebrafish

Gene: RERE

Gene alteration: The genetic change responsible for the babyface (bab) phenotype was identified. there are two bab alleles; babtb210 is caused by rerea Y361X, and babtw220c is caused by rerea Y394X

Model phenotype: Both models both display nearly identical phenotypes (Schilling et al.,1996) including a small head and eyes, severely reduced pharyngeal arches and pectoral fins, and enlarged ear capsules (Fig. 1A,B).

NonHumanModel Mus musculus

GeneAlteration oligonucleotide-directed mutagenesis of lambda phage to make a p.T494M vector to inject mice.

ModelPhenotype HP:0031531

HumanPhenotype HP:0000572

ModelEvidence Electron microscopy of retina showed degeneration of RPE indicated by abnormal basal morphology (fig. 5)

ModelVariant NM_004698.3(PRPF3):c.1481C>T (p.Thr494Met), 3352

Family#PresentingHPOs HP:0001999, HP:0003155, HP:0003124, HP:0003141, HP:0012347, HP:0012358, HP:0001399 (Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Increased LDL cholesterol, Abnormal protein N-linked glycosylation, Abnormal protein O-linked glycosylation, Liver failure)

HPOsFreeText elevated AT

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Turkish

Race n/a

Family#PreviousTesting Metabolic work up: Elevated AT, ALP, total cholesterol and LDL cholesterol, abnormal N- and O- glycosylation

Family#Method1 Sanger

Family#Method2 n/a

Family#GenotypingMethod Sanger on proband targeting CCDC115

Affected 2

Unaffected 0

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguinity

ProbandLabel F4-II1, male,9yo death

Case1PreviousTesting Metabolic results: AST 192–669 U/l[normal range, 0–50 U/l], ALT 83–308 U/l [normal range, 0–50 U/l], ALP 702 U/l[normal range, < 360 U/l]

Case2 F4-II2, female, 8yo diagnosis

Case2PreviousTesting Metabolic results: AST 98–422 U/l [normal range, 0–50 U/l], ALT 98–178 U/l [normal range, 0–50 U/l], ALP 710–985 U/l [normal range, < 360 U/l]. AT and CDG profile normalized after liver transplant.

Variant NM_032357.3(CCDC115):c.31G>T (p.Asp11Tyr), homozygous

ClinVar 218963

gnomAD n/a

VariantEvidence n/a

FamilyAddInfo n/a

FamilyPMIDs n/a

PMID: 29106755

Gene: HEXB

Disease: Sandhoff Disease

MonDO: MONDO:0010006

eLOD Family A-2.7, Family B-1.8

Variant Family A- NM_000384.2(APOB):c.9175C>T (p.Arg3059Cys) Family B-NM_000384.2(APOB):c.10182G>T (p.Lys3394Asn)

ClinVar A-69508, B-438310

CAID A-CA066337, B-CA345987169

gnomAD A-0.00003249 link B-n/a

CaseF9: Female, Italy, 48 years diagnosis

CasePresentingHPOs: HP:0001873 (Thrombocytopenia)

HPOsFreeText: World Health Organization bleeding score is 0 (1 members); Mean platelet count is 117 ×10^9/L; Mean platelet volume is 14.4 fL, Mean platelet diameter is 3.3 μm

CaseAddInfo: N/A

CaseF1:III-1: Female, Italy

CasePresentingHPOs: HP:0001634 (Mitral valve prolapse)

CaseAddInfo: Proband for F1

Case# Subject 2, F, 5mo died, Kurdish

CasePresentingHPOs HP:0001319, HP:0008872, HP:0002033, HP:0003128, HP:0002490, HP:0001531, HP:0040288, HP:0001712, HP:0001410, HP:0002098, HP:0002910, HP:0002126, HP:0000365, HP:0002151 (Neonatal hypotonia, Feeding difficulties in infancy, Poor suck, Hyperlactatemia, Increased CSF lactate level, Failure to thrive in infancy, Nasogastric tube feeding, Left ventricular hypertrophy, Decreased liver function, Respiratory distress, Elevated transaminases, Polymicrogyria, Deafness, Elevated serum lactate)

HPOFreeText: After caesarean delivery, neonatal hypotonia, poor feeding, and sucking. (3 months) failure to thrive, nasogastric feeding, left ventricular hypertrophy and impaired liver function. Brain MRI: bifrontal polymicrogyria and acoustic oto-emissions suggested deafness (4 months). Died of respiratory distress at 5 months.

CaseNotHPOs n/a

CasePreviousTesting Serum lactate (7.4 mmol/L; normal range 0.90–1.70 mmol/L), lactate to pyruvate ratio (170; normal range 30–50), CSF lactate (3.1 mmol/L; control < 2.2 mmol/L), liver function (AST: 84 UI/L, normal range 15–60; ALT: 52 UI/L, normal range 7–40; gGT: 262 UI/L, normal range 6–25 UI/L). Screened panel of known mitochondrial disease genes. Analysis of mtDNA and mtDNA copy number from patient muscle DNA were normal, thus excluding mtDNA rearrangements and point mutations.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with Sanger in patient and parents to confirm in trans

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

ClinVar 224316

gnomAD 0.0003508(Latino), 0.0001121(Total) -no homozygotes on record

VariantEvidence n/a

CaseAddInfo non-consanguineous, healthy older brother, c.542G>T variant in ExAC (10/120,324 alleles) and ESP6500 (1/11,824 alleles)

CaseAddPMIDs n/a

FamilyName: Family 3 (individuals 6 and 7)

FamilyPresentingHPOS: HP:0000639, HP:0012736, HP:0001252, HP:0001257

FamilyNotHPOs:

CountryOrigin: Saudi Arabia

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: MRI showed brain hypomyelination

FamilyGenotypingMethod: combination of homozygosity mapping and WES, autozygosity mapping

Affected: 3

Unaffected:

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo: consanguineous family

ProbandLabel: IV-6 (individual 6), Female, 6yo, dx at 1mo

Variant: NM_177400.2(NKX6-2):c.487C>G (p.Leu163Val)

ClinVar: 430623, https://www.ncbi.nlm.nih.gov/clinvar/variation/430623/

gnomAD: n/a

CasePresentingHPOs:

CasePresentingHPOTerm:

CaseNotHPOs:

AddCaseInfo:

VariantEvidence:

CasePt5 male, 15mo death, Italian

CasePresentingHPOs HP:0001987, HP:0001254, HP:0001252, HP:0003572, HP:0003217 (Hyperammonemia, Lethargy, Hypotonia, Low plasma citrulline, High plasma glutamine)

HPOsFreeText neonatal severe hyperammonemia, mildly hypotonic, lethargy, low plasma citrulline, elevated glutamine

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(6[normal 16-40μmol/l]), glutamine(1500[normal 530–913μmol/l]) and ammonia(1214[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.1440_1441del (p.Thr481CysfsTer?), 2. NM_001122634.3:c.3004C>T (p.Arg1002Trp) compound heterozygous

ClinVar n/a

CAID 1. CA2086366, 2. CA64748170

gnomAD 1. 0.00001802(European (Non-Finnish), 0.000008153(Total), 2. n/a

VariantEvidence n/a

CaseAddInfo Older brother who died with post-mortem suspicion of CPSD or NAGS deficiency.

CasePMIDs 21120950

Family#PresentingHPOs HP:0001987 (Hyperammonemia)

HPOFreeText: Severe hyperammonemia

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Italian

Race n/a

Family#PreviousTesting Elevated plasma ammonia in both siblings (3454 in Pt7 and 1858 in Pt8[normal<75 μg/dl]).

Family#Method1 PCR

Family#Method2 n/a

Family#GenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Affected 2

Unaffected n/a

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo n/a

ProbandLabel Pt7, Female, 5mo death

CasePresentingHPOs HP:0002283, HP:0100806, HP:0003572, HP:0003217 (Diffuse brain atrophy, Sepsis, Low plasma citrulline, High plasma glutamine)

CaseHPOsFreeText Severe hyperammonemia(2do), Severe diffuse brain atrophy on MRI(1mo), sepsis(5mo)

CasePreviousTesting Low plasma citruline(0[normal 16-40μmol/l]) and elevated glutamine(2488[normal 530–913 μmol/l])

Variant 1. NM_001875.4:c.1263+5G>C, 2. NM_001875.4:c.2429A>G (p.Gln810Arg)

ClinVar n/a

CAID 1. To register, 2. CA350440293

gnomAD n/a

VariantEvidence c.1263+5G>C causes a splice defect (Table 2)

FamilyAddInfo Brother, Pt8, died with similar clinical features and was diagnosed with CPS1D post-mortem.

FamilyPMIDs 12955727, 12655559

CasePt1 female, 3yo diagnosis, Italian

CasePresentingHPOs HP:0001508, HP:0002014, HP:0000505, HP:0002167, HP:0002013, HP:0001252, HP:0002321, HP:0001987, HP:0003217, HP:0002910, HP:0012747, HP:0100543, HP:0001256 (Failure to thrive, Diarrhea, Visual impairment, Speech impairment, Vomiting, Hypotonia, Vertigo, Hyperammonemia, Hyperglutaminemia, Elevated transaminases, Abnormal brain MRI signal intensity, Cognitive impairment, Mild ID)

HPOsFreeText normal psychomotor dev, failure to thrive and diarrhea(first years), visual/speech impairment, vomiting, hypotonia, vertigo(referred at 3y,2mo), , hyperammonemia, high glutamine, elevated transaminases, normal orotic levels, hyperintense signal in cortical-subcortical frontal region on brain MRI, cognitive impairment:IQ 53(3yo) mild ID(21yo)

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(17.3[normal 16-40μmol/l]), glutamine(1244[normal 530–913μmol/l]) and ammonia(300[normal< 75 μg/dl]), elevated transaminases 350 UI/L, normal orotic levels, CPS1 residual enzyme activity "low" in liver biopsy.

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4(CPS1):c.3047A>G (p.Asn1016Ser), 2. NM_001875.4:c.3500C>G (p.Thr1167Arg) compound het

ClinVar 1. 551211

CAID 2. CA350437190

gnomAD 1. 0.00006534(African), 0.000008123(Total) 2. n/a

VariantEvidence enzyme assay showing low CPS1 activity mentioned

CaseAddInfo n/a

CasePMIDs 21120950

PMID: 34694545

Gene: ICOSLG

Disease: Combined Immunodeficiency

MonDO: MONDO:0015131

InheritancePattern: Autosomal recessive

Notes:

Case#: G16221, 5yo at onset.

CasepresentingHPOs: HP:0000518,

CaseHPOfreeText: neural tumors, CNS and peripheral tumors.

CaseNotHPOs: HP:0010568, HP:0100014

CasePreviousTesting: SSCP analysis

CaseMethod1: Direct sequencing of both PCR strands

Variant: NR_156186.2:c.544C>T (nonsense)

CAID: CA323114415

CasePMIDs:

Gnomad: not found

CA3281989

Family#PresentingHPOs HP:0000639, HP:0007256, HP:0001251

FamilyNotHPOs HP:0001260, HP:0000486, HP:0001310

CountryOrigin Sweden

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod expanded pedigree confirmed to have SAMD9L variants with Sanger

Affected 5

Unaffected 9

Segregations 3*

AddSegregationInfo not to score

ProbandLabel Fam1:IV-3, Female, 38yo reported

Variant NM_152703.4(SAMD9L):c.2956C>T (p.Arg986Cys), NM_152703.3:c.689A>C(p.Asn230Thr)

ClinVar 446530(c.2956), CA368201553(c.689)

FamilyAddInfo at least one member with the variant who is unaffected, but likely due to age (4yo)

FamilyPMIDs 28202457

PMID:

Gene: PAX6

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

Disease: Ocular dysgenesis

InheritancePattern: AD

CaseP7 male, 59yo, 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: 5mL(lower reference limit: 1.5), sperm concentration: 15.5million/mL(reference: 15), total motility after 1hr: 4%(reference: 40), vitality: 47%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 95%, abnormal head morphology: 7%, abnormal base: 3%, absent flagella: 30.5%, short flagella: 25%, coiled flagella: 27%, flagella of irregular caliber: 33%, multiple anomalies index: 2.56%.

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

CaseP6 male, 28yo report, Tunisia

CasePresentingHPOs HP:0012207, HP:0003251

(reduced sperm motility, male infertility)

HPOsFreeText Patient's sperm volume: 3mL(lower reference limit: 1.5), sperm concentration: 7.8million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), normal spermatozoa: 0%(reference: 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

CaseP5 male, 31yo 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: 3.4mL(lower reference limit: 1.5), sperm concentration: 60million/mL(reference: 15), total motility after 1hr: 5%(reference: 40), vitality: 62%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 80%, abnormal head morphology: 8%, abnormal base: 2%, absent flagella: 24%, short flagella: 50%, coiled flagella: 8%, flagella of irregular caliber: 68%, multiple anomalies index: 2.5%.

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 nonconsanguineous

CasePMIDs 29449551

Case: Family J Proband JII-1, male, 12yo at report

CasePresentingHPOs: HP:0000953, HP:0030053, HP:0000998, HP:0000054, HP:0002240, HP:0031664, HP:0000365, HP:0012385, HP:0034373, HP:0001084, HP:0000771

CasePresentingHPOsFreeText: subcutaneous masses in genital area, dilated lateral scleral vasculature

CaseNOTHPOs: HP:0001822, HP:0000520, HP:0002619, HP:0007380, HP:0001256

CaseNOTHPOSFreeText:

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

CaseGenotypingMethod: Microarray, homozygosity mapping, haplotype analysis, direct sequencing of exons of SLC29A3

Variant: c.1045delC homozygous

ClinVarID: or CAID: 566/CA351488

gnomAD: The frameshift variant p.Leu349fs, located in exon 6/6, is present in gnomAD v4.0.0 with a MAF=0.000001799 (2/1112010 alleles) in the European Non-Finnish population and 0 homozygotes.

AddCaseInfo: Consanguineous, unaffected parents. 6 unaffected siblings

PreviouslyPublished: n/a

VariantEvidence: Kang et al. (2010; PMID: 20595384) performed functional characterization of the 1045delC mutation in Xenopus oocytes and observed near-total loss of transport activity compared to wildtype SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated mistrafficking of the mutant protein to the endoplasmic reticulum or Gogli apparatus

Case: Family H Proband HII-2, female, 50yo at report

CasePresentingHPOs: HP:0000823, HP:0002240, HP:0001822, HP:0034373, HP:0100490, HP:0002619, HP:0000520, HP:0001838, HP:0007380, HP:0001084, HP:0001871, HP:0004322, HP:0000135, HP:0000141, HP:0012410, HP:0011974

CasePresentingHPOsFreeText: stasis ulcers

CaseNOTHPOs: HP:0000953, HP:0000998, HP:0030053, HP:0001256

CaseNOTHPOSFreeText: dilated lateral scleral vasculature

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

CaseGenotypingMethod: Microarray, homozygosity mapping, haplotype analysis, direct sequencing of exons of SLC29A3, restriction digestion

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

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

AddCaseInfo: Consanguineous parents, not genotyped. 3 unaffected, not genotyped siblings

PreviouslyPublished: n/a

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

Case#: KMP 11, female, 57 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: yes

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

Case1: Female, Italy, Birth onset

CasePresentingHPOs: HP:0003798, HP:0002033, HP:0100703, HP:0000218, HP:0000689, HP:0000297, HP:0003325 (Nemaline bodies, Poor suck, Tongue thrusting, High-arched palate, Dental malocclusion, Facial hypotonia, Limb-girdle muscle weakness)

HPOsFreeText: N/A

CaseNotHPOs: HP:0003560, HP:0003715, HP:0001557, HP:0001270, HP:0002093, HP:0001627, HP:0000602, HP:0001283, HP:0002650, HP:0003306 (Muscular dystrophy, Myofibrillar myopathy, Prenatal movement abnormality, Motor delay, Respiratory impairment, Cardiac abnormality, Ophthalmoplegia, Bulbar palsy, Scoliosis, Spinal rigidity)

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Typical NM presentation, Parental segregation was confirmed

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

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

Variant1: NM_001164507.1:c.8899A>C (p.Thr2967Pro)

CAID: CA348807784 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.8899A%3EC

gnomAD: Not in gnomAD

Variant2: NM_001164507.1:c.23803_23806del (p.Arg7935Serfs*48)

CAID: CA758865527 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvsOrDescriptor=NM_001271208.2%3Ac.23908_23911del

gnomAD: Not in gnomAD

Case: Cecconi_Patient#903, female, 52 yrs old at onset of HCM

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOSFreeText:

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

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

Variant: c.488T>C p.(Leu163Ser)

ClinVarID: or CAID: 45784, CA282614

gnomAD: MAF=0.001724 in African/African Americans (43/24948 alleles), total allele frequency=0.0001521. No homozygotes. v2.1.1

AddCaseInfo: Pt has LVWT of 18, LVEF of 59%, and other medical issues (myasthenia gravis, T2DM, HepC, PVC, PACs, PSVT, and SND

PreviouslyPublished: no

VariantEvidence: none

Case: Zampieri SD1, Male

DiseaseAssertion: Sandhoff Disease

FamilyInfo: patient's genotype was confirmed in parents

CasePresentingHPOs: HP:0000007, HP:0033978

CaseHPOFreeText: neurological symptoms (unspecified)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: Patients presented with neurological symptoms and diagnosis was confirmed by the demonstration of reduced Hex A and Hex B activity in peripheral white blood cells or cultured fibroblasts.

GenotypingMethod: PCR

PreviouslyPublished: n/a

SupplementalData: n/a

Variant: c.534delAGTT (p.L178fs27X) in both alleles

CAID: CA560766108

gnomAD: MAF 0.000008937, European (non-Finnish), gnomAD variant ID: 5-73992535-CAGTT-C

VariantEvidence: PMID:11292324 previously reported this variant to be associated with the infantile form of SD. Genomic DNA amplification, heteroduplex analysis, cloning and sequencing revealed a 4-bp deletion in exon 4 at position 178. The result is a frameshift mutation that leads to a stop codon in exon 5. This mutation is associated with a dramatic decrease of HEXB mRNA levels.

6 individuals noted to have this variant in homozygosity. This is the same as the MPS registry number of homozygotes and uses the registry, so will only be scoring for Clarke et al. paper

Annotating here since the article is a PDF.

Case#: Lin ERT Proband, 3yo at dx, male, Taiwan

DiseaseAssertion: MPS1 H/S

FamilyInfo:

CasePresentingHPOs: HP:0002094, HP:0030828, HP:0002870, HP:0001640, HP:0001712, HP:0005133, HP:0001654, HP:0005145, HP:0008155, HP:0002653, HP:0002829, HP:0001376, HP:0002751, HP:0004348, HP:0007957, HP:0007663, HP:0002167, HP:0032341, HP:0410042

CaseHPOFreeText: Positive urine MPS screening test, blood IDUA activity=0.4 umol/h per mg protein (normal range 10-35). ERT improved cardiopulmonary status, joint range of motion, mobility, bone and joint pain, kyphoscoliosis, bone mineral density, sleep quality, corneal clouding and visual acuity, speech fluency, forced vital capacity and liver size, and resulted in 80.2% reduction in urinary GAG excretion. Cardiopulmonary failure

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: T364M homozygous

ClinVar: 11925

CAID: CA256126

SupplementalData: n/a

Case#: ATM02_V-3

Demographics: Male, 18 yrs at report

CasePresentingHPOs: HP:0000752, HP:0001581

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod:

Variant: NM_017890.4:c.6879delT

ClinVar:

CAID: CA4824093

gnomAD:

VariantEvidence: This variant has been reported in two apparently unrelated families of common ethnicity, and therefore likely founder mutation. Hence, the score is reduced from default.

CaseAddInfo:

CasePMIDs:

PMID: 28132693

Gene: ARHGEF18

Disease: Retinitis pigmentosa

MonDO ID: MONDO:0019200

Case# HondaF, female, newborn

CasePresentingHPOs HP:0001640, HP:0006682, HP:0011713, HP:0100572

CaseGenotypingMethod "gene analysis"

Variant NC_000003.10:g.14147425G>A

CAID CA052413

gnomAD 0.001044 link

CaseAddInfo 2 mutations in cis from mom, phenotypes described at birth (usually adult onset)

PMID: 14583446

Gene: GALNS

Disease: mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case: Family C/Prendiville Patient 2, Lebanese-Australian, 11yo at report

Not scoring this proband since this variant has been reported many times already and parents are consanguineous, from Lebanon which is near many of the other cases

Mouse models should potentially be downgraded given the significant difference in telomere biology

Case# II-4, Female, 14, Ireland

CasePresentingHPOs HP:0002506, HP:0002497, HP:0002061, HP:0011448, HP:0001347

CasePreviousTesting Initial genetic testing (with patient consent) included a screening panel for HSP, as well as SCA 1, 2, 3 and 6, all of which were negative.

CaseMethod1 WES

Variant NM_005186.3:c.1534C>T(p.Arg512Cys)

CAID CA6093457

gnomAD 0.000008977

Case# Patient 5, Caucasian, Female, age 61

CasePreviousTesting Screened for prevalent European mutations in apoB with DGGE.

CasePresenting HPOs HP:0005145 Narrowing of Coronary Artery and HP:0003124 Hypercholesterolemia

CaseNotHPOs n/a

CaseGenotypingMethod PCR fraction of exom 26, denaturing gradiant gel electrophoresis

Variant NM_000384.2(APOB):c.10580G>A (p.Arg3527Gln)

ClinVar 17890

gnomAD 0.0005791 gnomaD

VariantEvidence high LDL-cholesterol levels(mg/dl) P5=240, PMID: 3477815- reduced LDLR affinity

CaseAddInfo significantly lower fractional catabolic rate/production rate according to pending model

Case# Travaglini 1, Male, 16 report, Italian

CasePresentingHPOs HP:0006895, HP:0040083, HP:0001347, HP:0003487

CasePreviousTesting Sanger of SPG4 and 89 other known/candid genes by Nextera Custom Enrichment panel

CaseMethod1 Sanger Sequencing

CaseGenotypingMethod CAPN1 variants found in same panel screen

Variant NM_005186.3:c.221G>A (p.G74D), NM_005186.3:c.911C>T(p.T304M), NM_005186.3:c.1418G>T (p.R473L)

CAID CA6092976, CA6093221, CA6093432

gnomAD 0.0006904 , 0.0003415, 0.00003952

CaseAddInfo nonconsanguineous family

Cultured patient fibroblasts showed disappearance of filamentous mitochondria in favor of fragmented and punctuated mitochondria and a 20% decrease of mitochondrial content in fibroblasts.

Case3: Male, 41 yrs report

CasePresentingHPOs: HP:0012432, HP:0003738, HP:0003236, HP:0003273, HP:0003044, HP:0012785, HP:0006466, HP:0005997, HP:0003798, HP:0100295, HP:0031237, HP:0003201, HP:0012548 (Chronic fatigue, Exercise-induced myalgia, Elevated serum creatine phosphokinase, Hip contracture, Shoulder flexion contracture, Flexion contracture of finger, Ankle contracture, Neck flexion contracture, Nemaline bodies, Muscle fiber atrophy, Internally nucleated skeletal muscle fibers, Rhabdomyolysis, Skeletal muscle fatty infiltration)

HPOsFreeText: Jaw contractures, Core-like regions

CaseNotHPOs: HP:0001627 (Cardiac abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Variant is confirmed de novo via parental testing

CasePreviousTesting: ACTA1 and TPM3 were 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

Case2: Male, 14 yrs report

CasePresentingHPOs: HP:0002355, HP:0002527, HP:0000023, HP:0001763, HP:0002942, HP:0001276, HP:0006466, HP:0003089 (Difficulty walking, Falls, Inguinal hernia, Pes planus, Thoracic kyphosis, Hypertonia, Ankle contracture, hamstring contracture)

HPOsFreeText: In-toe gait, Tendo-Achilles release performed

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Son of Case 1, Variant is de novo in mother

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#: II.4 - male, 23, European descent II.5 - male, 28, European descent CasePresentingHPOs: Both patients II.4 and II.5 - HP:0003233 (low HDL cholesterol), HP:0012153 (hypotriglyceridemia), HP:0003563(decreased LDL cholesterol)

CaseMethod1: Exome CaseMethod2: Sanger

Variant: NM_014495.3(ANGPTL3):c.385G>T (p.Glu129Ter) and NM_014495.3(ANGPTL3):c.50_51delCCinsGA (p.Ser17Ter)

ClinVar: 18439 (p.Ser17Ter), 18440 (p.Glu129Ter), for both variants - 1 assertion for pathogenic based on OMIM but no assertion criteria provided

gnomAD: not in gnomAD

VariantEvidence: 12 other individuals from the Dallas Heart Study with ANGPTL3 frameshift mutations with phenotypes in Supplementary doc (PMID 19075393), additive dosage model with 2 mutations, 1 mutation and 0 (in supplementary table 5), “key enzymes in the metabolism of circulating triglycerides and HDL cholesterol, respectively, are elevated in Angptl3-knockout mice, suggesting that increased activity of these enzymes may explain the low levels of triglycerides and HDL cholesterol in humans with ANGPTL3 nonsense mutations” (PMIDs 17110602, 12097324, and 17681148)

Case4: Male, Spain, Post-birth onset

CasePresentingHPOs: HP:0003798, HP:0001324, HP:0000297, HP:0003701, HP:0001252, HP:0001284, HP:0002307, HP:0000218, HP:0001382 (Nemaline bodies, Muscle weakness, Facial hypotonia, Proximal muscle weakness, Muscular hypotonia, Areflexia, Drooling, High palate, Joint hypermobility)

HPOsFreeText: Cephalic support, Sedestation

CaseNotHPOs: HP:0000602, HP:0001249, HP:0001627, HP:0002093, HP:0002307, HP:0003722, HP:0002460, HP:0001283, HP:0002650, HP:0002540, HP:0006466, HP:0011471 (Ophthalmoplegia, Intellectual disability, cardiac abnormality, Ankle contracture, Drooling, Neck flexor weakness, Distal muscle weakness, Bulbar palsy, Respiratory insufficiency, Inability to walk, Scoliosis, PEG-fed in infancy)

NotHPOsFreeText: Bimodal communication, Wheelchair dependence, Mechanic ventilation

CaseAddInfo: Typical variant, Paternity/maternity was confirmed, cDNA analysis confirmed that Variant 1 results in a splice-site donor mutation which skips exon 24 which was confirmed by Sanger sequencing and leads to this deletion: p.His738_Asp770del (c.2212_2310del)

CasePreviousTesting: N/A

CaseGenotypingMethod: A research panel with 751 genes relating to neurological disorders, including the coding and intronic flanking regions of ACTA1, CFL2, KBTBD13, NEB, TNNT1, TNNT3, TPM2 and TPM3, was used to locate any variants in the proband. These variants were then prioritized and confirmed by Sanger sequencing in the probands and their relatives.

Variant1: NM_001164507.1:c.2310+5G>A (p.=)

CAID: CA913203562 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203562

gnomAD: Not in gnomAD

Variant2: NM_001164507.1:c.17779_17780del (p.Tyr5927Hisfs*17)

CAID: CA913203561 http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913203561

gnomAD: Not in gnomAD

Transfection into COS-7 cells showed that this variant has 1.2% IDUA activity compared to WT

PMID: 29801986

Gene: CPS1

Disease: Carbamoyl phosphate dehydrogenase deficiency

MONDO:0009376

InheritancePattern: AR

CaseFSIP2_1 male, 44yo report, Tunisian

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

(male infertility, asthenospermia, sperm tail anomaly)

HPOsFreeText Sperm volume: 2.5mL, sperm concentration: 6.7 million/mL, total motility: 1h, vitality: 47%, normal spermatozoa: 0%, absent flagella: 2%, short flagella: 32%, coiled flagella: 26%, flagella of irregular caliber: 57%

CaseNotHPOs n/a

CasePreviousTesting Previous genetic analysis of DNAH1, CFAP43, and CFAP44 did not end in diagnosis. "Normal somatic karyotypes 46,XY and were negative for Y chromosome microdeletions."

Variant NM_173651.3(FSIP2):c.910del (p.Gln304Lysfs)

ClinVar 586972

gnomAD not in gnomAD

CaseAddInfo Consanguineous parents

CasePMIDs 29449551

Case: Mohlo-Pessach Patient 2, male, 20yo at report, Arab

CasePresentingHPOs: HP:0000365, HP:0000953, HP:0000998, HP:0004322, HP:0001999, HP:0000494, HP:0003196, HP:0000463, HP:0001084, HP:0001433, HP:0100490, HP:0001935, HP:0003565, HP:0011227, HP:0002716, HP:0100727

CasePresentingHPOsFreeText: Cutaneous induration and hyperpigmentation of the thighs appeared at 8yo, spread to genitals, back, and lower limbs. Retrognathism. Scrotal masses. Fixed flexion contractures of the proximal interphalangeal joints of the right fourth and fifth fingers and the left fifth finger. Skin biopsy included dermal infiltrate consisting of lymphocytes, plasma cells and CD68+ histiocytes, and dermal and subcutaneous fibrosis.

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting:

CaseGenotypingMethod: SLC29A3 exons and splice junctions were PCR-amplified using intronic primers. PCR products were purified and sequenced on ABI 3700 capillary sequencer.

Variant: c.1088G>A (p.Arg363Gln)

ClinVarID: or CAID: CA129562

gnomAD: This missense variant, Arg363Gln, is present in gnomAD v4.0.0 with a MAF=0.0002666 (16/60010 alleles) in the Admixed American population and 0 homozygotes.

AddCaseInfo: consanguineous parents

PreviouslyPublished: n/a

VariantEvidence: n/a

Cell transfection assays showed marked exon 2 skipping in these assays, but also yielded a large fraction of normal transcripts.

c.51+3A>G mutation cosegregates with low C1 inhibitor protein levels in one family. alternative splicing of exon 3, found in peripheral blood cell mRNA but not in the liver or in hepatoma cell lines and we show that, in cultured monocytes of a patient carrying the c.51+3A>G mutation, this alternative splicing is shifted from exon 3 exclusion to skipping of both exons 2 and 3

Variants: c.51+3A>G; c.51+5G>A

CAIDs: CA2579981804; error in CAR-unable to register

MiltingF1

FamilyNotHPOs HP:0100660, HP:0004756, HP:0001645, HP:0031317

CountryOrigin Germany

Ethnicity Danish

Family#PreviousTesting: whole genome Family#Method1 PCR

Family#GenotypingMethod Liquid Chromatography screening

Affected 8

Unaffected 6

Segregations 7

eLOD 2.1

ProbandLabel Milting3:1 female

Variant NM_024334.2(TMEM43):c.1073C>T (p.Ser358Leu)

ClinVar 734

Case: TTD218UT

Demographics: Female, 1.5 years at diagnosis. Moroccan origin.

CasePresentingHPOs: HP:0004779, HP:0045055, HP:0008064, HP:0000252, HP:0001263, HP:0004322, HP:0001935, HP:0004840, HP:0040082, HP:0100025

Individual showed recurrent aggravation of hair-loss by tufted breakage at the scalp boundary immediately following episodes of infection-induced fever, and upon long-term exposure to the heat of the sun, she appears to have increased hair-loss. She had an IQ of 54 (at 7 years) and limited physical endurance.

CaseNOTHPOs: Progressive deterioration at 8 years

CasePreviousTesting: None

CaseGenotypingMethod: Whole genome sequencing, confirmed by Sanger sequencing.

Variant: NM_002095.5(GTF2E2):c.C559T [p.Asp187Tyr]

ClinVar ID: 225841

Pathogenic, non-LOF variant gnomAD: hypomorphic, homozygous missense. Not in gnomAD.

AddCaseInfo: The parents of this individual were consanguineous and were heterozygous for the mutation. Of 3 siblings, two (a brother and a sister) were found to be heterozygous carriers, while one was found to have the homozygous wild type alleles (a sister).

VariantEvidence: The variant has been previously reported by Kauschal et al (26996949) in a 16-yr old Moroccan girl. The identification of this variant in four individuals of Moroccan origin suggests the possibility of a founder mutation. Since the variant has been already scored, this proband is not being scored.

Case: Family 11 GC21390 Proband II:1, 49yo at onset (incidental finding), 56yo at report

CasePresentingHPOs:

CasePresentingHPOsFreeText: Prolonged dark adaptation, peripheral visual field loss, BCVA= 6/9, 6/5, retinitis pigmentosa, hypertension, plasma coQ10 level=582.28nmol/L (Reference range: 227- 1432 nmol/L)

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: negative IRD gene panel analysis

CaseGenotypingMethod: genome sequencing, direct Sanger

Variant: c.933delC p.(Tyr311); c.682-7 T > G p.(Gln230); p.(Leu193Phefs*27)

ClinVarID: or CAID: CA6828694; CA6828747

gnomAD: This nonsense variant, Tyr311Ter in exon 7/7, is present in gnomAD v4.1.0 with a MAF=0.00002627 (31/1179996 alleles) in the European NF population with 0 homozygotes. The score has been reduced since NMD is not expected to occur.

This non-canonical splice site variant, c.682-7T>G, is present in gnomAD v4.1.0 with a MAF=0.001031 (66/64040 alleles) in the European Finnish population with 0 homozygotes.

AddCaseInfo: only family member noted to be affected, mother was unaffected and heterozygous for tyr311ter but father is deceased and not genotyped

PreviouslyPublished: n/a

VariantEvidence: RT-PCR of patient blood derived mRNA using oligonucleotide primers targeting COQ5 (Supplementary Table 6) followed by agarose gel electrophoresis showed definite altered transcript length and mis-splicing for the COQ5 c.682-7 T > G variant. ONT sequencing of the full COQ5 transcript from whole blood of individual family 11, II:1 showed skipping of exon 5 to be the predominant effect of the c.682-7 T > G variant leading to early termination and probable nonsense-mediated decay (p.(Gln230)) (Fig. ​(Fig.4).4). In addition, exon 4–5 skipping was identified in a low proportion of reads (3%) leading to a reading-frame shift and early termination (p.(Leu193Phefs27)).

Case: Individual 3, male, 7.5 yo

CasePresentingHPOs: HP:0000750, HP:0001263, HP:0001290, HP:0002360, HP:0007018, HP:0000736, HP:0004673, HP:0000735, HP:0000629, HP:0000316, HP:0004209, HP:0001212, HP:0001382,

CasePResentingHPOText: Subject began walking at 18 months. Testing for autism gave the following results: WPPSI-III-NL: TIQ 98, VIQ 106, PIQ 96.

CaseNOTHPOs: HP:0001250, HP:0002376, HP:0000202, HP:0000504,

CasePreviousTesting: Metabolic screening, SNP-array, and Fragile X (FMR1) testing were normal

CaseGenotypingMethod: Trio-WES. Individual is noted as being mosaic (60%) for the FBXO11 mutation. Testing also identified a VUS in TP73 (NM_0054 27.3):chr1: g.3644250 G>A, c.901G>A; p.(Asp301Asn). Not noted as de novo, so assume inherited and parents were not noted as having behavioral abnormalities or intellectual disability.

Variant: hg19:chr2: g.4806611 8=/T>C, c.467=/A> G p.(Gln156Arg) or NM_001190274.1:c.467A>G

CA ID: CA346813225

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

gnomAD: n/a

AddCaseInfo:

VariantEvidence: Individual is noted as being mosaic (60%) for the FBXO11 mutation. Gln156 is located just N-terminal to the F-box region of FBXO11, and is conserved across species. Pathogenicity algorithms showing varying predictions, from tolerated to damaging, thus indicating a VUS. No functional assays were performed to indicate the impact of the Q156R mutation on FBXO11 function.

PMID: 24172204

GeneName: SLC29A3

HGNC: HGNC:23096

Disease: H syndrome

MonDO ID: MONDO:0011273

Inheritance: AR

great review of cases to curate

Case: Patient 1, female, AOR 2 years, Turkish

CasePresentingHPOs: HP:0001561, HP:0003265, HP:0001270, HP:0000924, HP:0000253, HP:0002007, HP:0000520, HP:0005280, HP:0003196, HP:0000463, HP:0005306, HP:0000212, HP:0000347, HP:0005619, HP:0002938, HP:0000960, HP:0009826, HP:0001156, HP:0004060, HP:0100543, HP:0008936, HP:0007340, HP:0001265, HP:0005193, HP:0002063, HP:0002240, HP:0001407, HP:0100625, HP:0004565, HP:0005619, HP:0002867, HP:0100865, HP:0003016, HP:0003416, HP:0002176, HP:0006532, HP:0000670, HP:0004315, HP:0002850,

CaseNOTHPOs: HP:0000365, HP:0000504

CasePreviousTesting: Lab examines including urine organic acid analysis (urine glycosaminoglycan/ GAG and lysosomal enzymes), tandem mass screening, chromosome analysis, electroencephalogram were unremarkable. Negative for mutations in SLC35D1 (Schneckenbecken dysplasia MIM 269250), and INPPL1 (opsismodysplasia; MIM 258480) .

CaseGenotypingMethod: WES

Variant: NM_001440.3: c.953C>T(p.P318L)

CA ID: CA370858101

Homozygous

gnomAD: no homozygotes, only 2 hets in Euro-ND populatin CA370858101

AddCaseInfo: Parents were also tested by WES and were both found to be carriers of the mutation.

VariantEvidence: WEstern blot analysis of EXTL3 from patinet 1 cells shows expression of hte P318L variant (Figure 1B), indicating the protein is still produced. However, a glycosyltransferase assay using the wildtype EXTL3 and th eP318L variant showed reduced enzyme activity in the P318L variant compared to wildtype, and simiar levels of activity as untransfected/ mock controls. This indicates the P318L mutation acts as a loss of protein function of the enzyme activity.

Case# Baskin RW, Female, 31

CasePresentingHPOs HP:0004756, HP:0011841, HP:0002013

CasePreviousTesting patients referred to our high-risk hereditary heart disorders clinic for assessment of possible ARVC, as well as DNA-bearing blood or tissue samples sent for clinical ARVC gene-testing from other physicians, clinics or institutions to our CLIA-approved molecular genetics laboratory at the Hospital for Sick Children (listed on www.genetests.org).

CaseMethod1 PCR

CaseGenotypingMethod direct sequence analysis of all exons and flanking intron sequences of DSP (MIM 125647), PKP2 (MIM 602861), DSC2 (MIM 125645), DSG2 (MIM 125671) and TMEM43.

Variant NM_024334.2(TMEM43):c.934C>T (p.Arg312Trp)

ClinVar 36873

gnomAD 0.03553 link