PMID 28813500

Variant c.3268G>A

Phenotypes HP:0001402, HP:0001394

Phenotypes free-text hepatocellular carcinoma, cirrhosis

Case#: G170692, 4yo at onset.

CasepresentingHPOs:

CaseHPOfreeText: neural tumors

CaseNotHPOs: HP:0100014, HP:0000365, HP:0000518

CasePreviousTesting: SSCP analysis

CaseMethod1: Direct sequencing of both PCR strands

Variant: NM_000268.3:c.551G>A (nonsense)

CAID: CA411142590

Gnomad: not present

Variant NM_144668.5:c.3007_3337del

ClinVar 586974

CaseP1 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: 4mL(lower reference limit: 1.5), sperm concentration: 11.3 million/mL(reference: 15), total motility after 1hr: 2%(reference: 40), vitality: 53%(reference:53%), normal spermatozoa: 0%(reference: 4), abnormal acrosome: 66%, abnormal head morphology: 42%, abnormal base: 36%, absent flagella: 31%, short flagella: 34%, coiled flagella: 20%, flagella of irregular caliber: 4%, 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 gomAD

CaseAddInfo consanguinity

CasePMIDs 29449551

Case: Family 2 Kismet Proband, Turkish, male

CasePresentingHPOs: HP:0000407, HP:0002240, HP:0004322, HP:0025289, HP:0033176, HP:0100727

CasePresentingHPOsFreeText: Rapidly growing orbital mass with SHML histopathology. Retropharyngeal lymphadenopathy. Filling of lymph node sinuses with histiocytes, plasma cells and lymphocytes. Histiocytes had a benign appearance, were CD-1a negative but positive for CD68 and S-100.

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: direct sequencing of PRF1 and UNC5B

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

Variant: p.Gly437Arg; p.Phe103X

ClinVarID: or CAID: 565; 30947

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.

The nonsense variant, p.Phe103Ter found in exon 2/6, is present in gnomAD v4.0.0 with a MAF=0.0005201 (3/5768 alleles) in the Middle Eastern population and 0 homozygotes.

AddCaseInfo: 2 affected brothers

PreviouslyPublished: 16118898

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)

MonDO: MONDO:0032706

Case: Patient AW, Belgian female developed mild gait imbalance at age 38 years with progressive decline with clear dementia at age 53 years. She died at age 62 years due to infectious complications. Homozygous for GCAP2:c.1198_1199insG; p.(His400fs*15). The variant and its segregation were confirmed in the proband and her daughter using standard Sanger sequencing methodology.

DiseaseAssertion: Cerebellar ataxia

FamilyInfo: No consanguineous family. Her brother died from brain tumor, her father had epilepsy and died at 84 years old, her mother was alive without ataxia or gait disorder at age 85 years. Daughter is healthy.

CasePresentingHPOs: HP:0002141, HP:0007240, HP:0001348, HP:0033687, HP:0000708, HP:0002061, HP:0002540, HP:0001268, HP:0000741, HP:0000718, HP:0000716, HP:0002546, HP:0002015, HP:0002300, HP:0000726 (Gait imbalance, Progressive gait ataxia, Brisk reflexes, Short term memory impairment, Atypical behavior, Lower limb spasticity, Inability to walk, Mental deterioration, Apathy, Aggressive behavior, Depression, Incomprehensible speech, Dysphagia, Mutism, Dementia

CaseHPOFreeText: Speech problems, jerky eye movements, dysexecutive syndrome, bed ridden

CaseNOTHPOs: HP:0000639 (Nystagmus)

CasePreviousTesting: Brain MRI at age 53 years revealed severe atrophy of the cerebellum, both vermian and hemispheric, mainly of the superior aspect, and also global cerebral atrophy (cortical and central). Levels of alpha-fetoprotein, vitamin E, copper, and folic acid were normal. Screening for trinucleotide repeat expansions was negative for SCAs 1, 2, 3, 6, 7, 8, 10, 12, and 17, and for Friedreich’s ataxia. Post-mortem brain examination revealed cerebellar atrophy in combination with a mild atrophy of the pes pontis. Normal nerve conduction studies. Normal opthalmological evaluation.

GenotypingMethod: Exome sequencing. Sanger sequencing was performed for confirmation of the variants and for segregation analyses using standard techniques. 90 560 single-nucleotide variations and 8961 indels were called. No obvious variants in known ataxia genes were observed. Variants were filtered for variant type, rarirty (MAF <0.5%) and conservation (>0.75, phyloP). Trio-sequencing analysis to detect putativede novo variants was not possible because of the unavailability of paternal DNA for Patient NIJ and parental DNA for Patient AW.

Variant: c.1198_1199insG; p.(His400fs*15) Homozygous

ClinVarID: 624620

CAID: CA30125084

gnomAD: Total AF 0.000004342, gnomAD v4.1. https://gnomad.broadinstitute.org/variant/1-117883536-T-TC?dataset=gnomad_r4

Functional evidence: Drosophila fly GDAP2 model supports a role of GDAP2 in motor behaviour and suggests that cellular stress might be driving the neurodegenerative cascade. Ubiquitous Gdap2 RNAi-1 knockdown results in droopy wings. Gdap2 knockdown does not result in increased levels of apoptotic cell death in central brain upon 18 hours paraquat exposure.

Case# Subject 4, M, 8yo onset, Hispanic

CasePresentingHPOs HP:0001249, HP:0001289, HP:0002066, HP:0009053, HP:0007340, HP:0001987, HP:0002925, HP:0005184, HP:0002058, HP:0002169, HP:0003201, HP:0001250, HP:0003236, HP:0000821, HP:0006801

HPOcont: Intellectual Disability, Confusion, Gait ataxia, Lower limb muscle weakness, Dysarthria, Hyperammonemia, Elevated TSH, Prolonged QTc interval, Myopathic facies, Clonus, Rhabdomyolysis, Seizures, Elevated CPK, Hypothyroidism, Brisk DTR

HPOFreeText: (2 years) uncoordinated gait and intellectual disability. (8 years) disorientation, ataxic gait, weakness in lower extremities, and dysarthria. (12 years) myopathic facies, brisk tendom reflexes, clonus, and impaired gait.

CaseNotHPOs HP:0001943, HP:0002151, HP:0002913

NotHPOcont: Hypoglycemia, Elevated Lactate, Myoglobinuria

CasePreviousTesting "lactate and glucose normal; elevated ammonia(111 μmol/l), elevated CPK (16,674 U/l). Urine was negative for myoglobin. TSH level was increased to 30.8 μIU/ml (range 0.32–5.00 μIU/ml), T3 was 166 ng/dl (range 90–260 ng/dl), and T4 was 5.2 μg/dl (range 6.4–13.3 μg/dl). Urine organic acids were normal."Muscle biopsy showed normal respiratory chain studies. Mitochondrial genome sequencing for common point mutations and deletions were normal."

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES and cSNP results confirmed with Sanger

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

ClinVar (1) 208823

CAID (1) CA358646

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

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

CaseAddInfo nonsanguineous, confirmed heterozygosity of both parents

CasePMIDs n/a

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

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

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

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

CaseNotHPOs HP:0001250

NotHPOcont: Seizures

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

CaseMethod1 WES

CaseMethod2 PCR

CaseGenotypingMethod WES and cSNP array, validated deletion variant with PCR

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

ClinVar (1) 208823

CAID (1) CA358646

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

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

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

CasePMIDs n/a

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

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

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

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

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

NotHPOcont: Seizures, Arrhythmia, Rhabdomyolysis

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

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod WES and cSNP array

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

ClinVar 521699

CAID CA358646

VariantEvidence splice site

CaseAddInfo consanguineous parents

CasePMIDs n/a

CaseA032-IV-1 male, unknown age, Han Chinese

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

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

HPOsFreeText Table S1: Sperm volume: 1.1mL, sperm concentration: 15.5million/mL, progressive motility: 1.5%, motility: 9.5%, normal spermatozoa: 7.0%, absent flagella: 12.0%, short flagella: 55.0%, coiled flagella: 23.0%, angulation: 1.0%, irregular caliber: 2.0%. Semen volume and sperm concentration were normal to the standards.

CaseNotHPOs n/a

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

Variant 1. NM_144668.5:c.415C>T(p.Gln139Ter), 2. NM_144668.5:c.1722del(p.Phe574LeufsTer3)

ClinVar 1. n/a, 2. n/a

CAID 1. CA387002758, 2. CA891834513

gnomAD 1. Maximum population minor allele frequency in gnomAD = 0.00005574 (East Asian); no homozygotes, 2. not in gnomAD

CaseAddInfo phase confirmed in parents, in trans in patient

CasePMIDs n/a

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

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

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

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

CaseNotHPOs n/a

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

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

ClinVar n/a

CAID CA6840411

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

CaseAddInfo parents unavailable for testing

CasePMIDs n/a

Family L has this variant segregating through

Family A autosomal recessive variant found in CHST9 (MIM: 610191; c.1133A>G [p.Asn378Ser] [GenBank: NM_031422])

PMID: 28132690

Gene: EXTL3

Disease: Neuro-immuno-skeletal Dysplasia Syndrome

MonDO ID: n/a

OMIM: 617425

ExperimentName: Ojala 2016 hiPSC-derived CMs

PatientCell: CL_0002620 (skin fibroblasts)

GeneFunction: GO:0008016 (regulation of heart contraction)

GeneAlteration: hiPSC-derived cardiomyocytes (CMs) generated from skin fibroblasts collected from patients carrying a TPM1-Asp175Asn mutation

FunctionalEvidence: Figure 2 shows enlarged cardiomyocytes (CMs) (a-b), an increase in multinucleated CMs (c), and calcium handling abnormalities (d) for the HCM-TPM1 variant CMs compared to WT CMs.

FAVariants: NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn), CA018106

Case2: Female, Birth onset

CasePresentingHPOs: HP:0002093, HP:0002938, HP:0002015, HP:0003798, HP:0003200, HP:0003548 (Respiratory insufficiency, Lumbar hyperlordosis, Dysphagia, Nemaline bodies, Ragged-red fibers, Subsarcolemmal accumulations of abnormally shaped mitochondria)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Mother of proband

CasePreviousTesting: N/A

CaseGenotypingMethod: See Family

Variant: NM_003289.3:c.397C>T (p.Arg133Trp)

ClinVar: 12463 https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/

gnomAD: Not in gnomAD

Case1: Female, Birth onset

CasePresentingHPOs: HP:0008947, HP:0008872, HP:0002033, HP:0030043, HP:0001349, HP:0001488, HP:0010804, HP:0002650 (Infantile hypotonia, Feeding difficulties in infancy, Poor suck, Hip subluxation, Facial diplegia, Bilateral ptosis, Tented mouth, Scoliosis)

HPOsFreeText:Disorganized myofibrils and thickened Z bands

CaseNotHPOs: HP:0003798 (Nemaline bodies)

NotHPOsFreeText: N/A

CaseAddInfo: Proband of Family 1

CasePreviousTesting: N/A

CaseGenotypingMethod: See Family

Variant: NM_003289.3:c.397C>T (p.Arg133Trp)

ClinVar: 12463 https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/

gnomAD: Not in gnomAD

PMID: 27825773

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Important citations to study how TERC relates to genetic anticipation (inheriting not only TBD genes but short telomeres to begin with, leading to earlier onset)

Case#: Family 1, Individual III-1, Female, 27 yo, dx at 3 months old

CasePresentingHPOs: HP:0000639, HP:0001332, HP:0001270, HP:0002497, HP:0001272, HP:0002062, HP:0000571, HP:0002540, HP:0000511, HP:0012547, HP:0001260, HP:0030187, HP:0001332, HP:0000473

CaseNotHPOs: HP:0003474, HP:0007108

CasePreviousTesting: MRI showing brain hypomyelination

CaseGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

gnomAD: n/a

VariantEvidence:

CaseAddInfo: Wheelchair bound at 27 yo

CasePMIDs:

Families 1 and 2

NKX6-2: c.121A>T; p.Lys41∗ (NM_177400.2) absent from gnomAD and has not previously been linked to human phenotypes.

FamilyName: Family 2

FamilyPresentingHPOS: HP:0002497, HP:0003429

FamilyNotHPOs:

CountryOrigin: Kenya and Tanzania

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: MRI showed brain hypomyelination

FamilyGenotypingMethod: combination of homozygosity mapping and WES, haplotype analysis

Affected: 2

Unaffected:

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo:

ProbandLabel: III-2 (individual 4), Female, 44yo, dx at 1yo

Variant: NM_177400.2(NKX6-2):c.121A>T (p.Lys41Ter)

ClinVar: 430622, https://www.ncbi.nlm.nih.gov/clinvar/variation/430622/

gnomAD: n/a

CasePresentingHPOs: HP:0000639, HP:0002066, HP:0002061, HP:0001272, HP:0007366, HP:0002540, HP:0000473, HP:0002451, HP:0002599, HP:0000571, HP:0000666, HP:0000496, HP:0002078, HP:0002070, HP:0008969, HP:0001348

CasePresentingHPOTerm: nystagmus, gait ataxia, lower limb spasticity, cerebellar atrophy, brainstem atrophy, inability to walk, cervical dystonia, lower limb dystonia, head titubation, hypometric saccades, horizontal nystagmus, limited eye movements, truncal ataxia, limb ataxia, lower limb stiffness

CaseNotHPOs: HP:0011730

AddCaseInfo: Cousin with identical phenotype died due to tuberculosis in childhood. (Individual 5)

VariantEvidence:

Family 3

Variant, (NM_177400.2; c.487C>G; p.Leu163Val), replaces conserved leucine within the first helix of the homeodomain, therefore destabilizing the protein.

Case#: Vazna Patient #15, female, Czech Republic or Slovakia, onset in infancy, 10mo at dx, 12yo at report

DiseaseAssertion: MPS1, H/S

FamilyInfo:

CasePresentingHPOs: HP:0008301, HP:0002159, HP:0000280, HP:0000943, HP:0007957, HP:0004322, HP:0000256, HP:0001387, HP:0001263, HP:0001433, HP:0031664, HP:0000023, HP:0000158

CaseHPOFreeText: Deficiency of IDUA activity in leukocytes showed either no or very low residual enzyme activity (no exact amount specified), systolic murmur 3–4/6. After ERT: decreased illness (obstructive bronchitis), decreased excretion of GAGs in the urine, decreased organomegaly, increased mobility

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: n/a

GenotypingMethod: Direct sequencing of PCR products

PreviouslyPublished: n/a

Variant: p.Q70X (pathogenic); p.R628X. Compound heterozygosity was confirmed by analysis of parental samples. Also has p.A8, p.A20, p.Q33H, p.L118

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

NonHumanModel: Zhang_Mouse

GeneAlteration: Exon 2 of RAB39B was targeted using two gRNAs and Cas9 mRNA in the C57BL/6N background. Mice harboring 397-bp deletions in exon 2 were obtained.

ModelPhenotype: HP:0000256 Social and memory deficits

HumanPhenotype: HP:0001249, HP:0000256

ModelEvidence: Similar to PMID: 33364235, authors show through ASD-related tests that KO mice exhibit social and memory deficits. They also show that RAB39B variation results in over-proliferation and differentiation deficits of neural progenitor cells, which results in larger that normal number of neurons. Mice therefore have macrocephaly.

ModelVariant:

WhereInPaper:

The model is scored reduced points as the mice recapitulate the ASD phenotype seen in some human patients with RAB39B variants, but does not provide evidence for the Parkinson disease phenotype. (0.5)

Family#PresentingHPOs HP:0003155, HP:0010837, HP:0003124, HP:0001397, HP:0010836, HP:0003141, HP:0012347, HP:0012358, HP:0001976 (Elevated alkaline phosphatase, Low ceruloplasmin, Elevated cholesterol, Steatosis, Abnormality of copper homeostasis, Elevated LDL-C, Abnormal N-glycosylation, Abnormal O-glycosylation, Reduced antithrombin III activity)

HPOsFreeText Elevated amino transferases, minimal fibrosis, slightly decreased coagulation factors XI, XIII, and antithrombin-III

FamilyNotHPOs HP:0200032 (Kayser-Fleischer rings)

CountryOrigin n/a

Ethnicity Greek

Race n/a

Family#PreviousTesting Metabolic work up and anyalysis of coagulation factors, the latter of which showed decreased antithrombin-II, factor XI, factor XIII, and protein S, type 2 CDG. No mutations found in ATP7B, Wilson's disease excluded.

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod WES on siblings, confirmed heterozygous in parents with Sanger

Affected 2

Unaffected 2

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo consanguineous

ProbandLabel F1-II2, male, 14yo report

Case1PreviousTesting Serum ALT 54 U/l [normal range, 0–50 U/l], AST 73 U/l [normal range, 0–50 U/l], ALP 745 U/l [normal range, < 360 U/l], ceruloplasmin 11.5 mg/dl [normal range, 15–60 mg/dl], urine copper/creatine ratio 86.9 μg/g [normal range, < 60 μg/g], cholesterol 253 mg/dl [normal range, 120–200 mg/dl], LDL cholesterol 188 mg/dl [normal range, 50–130 mg/dl]

Case2 F1-II3, male, 6yo report

Case2PreviousTesting ALT 210 U/l [normal range, 0–50 U/l], AST 246 U/l [normal range, 0–50 U/l], ALP 1162 U/l [normal range, < 360 U/l], ceruloplasmin 15.6 mg/dl [normal range, 15–60 mg/dl], urine copper/creatine ratio 72.8 μg/g [normal range, < 60 μg/g], cholesterol 336 mg/dl [normal range, 120–200 mg/dl], LDL cholesterol 277 mg/dl [normal range, 50–130 mg/dl]

Variant NM_152464.2(TMEM199):c.20C>A (p.Ala7Glu), homozygous

ClinVar 218965

gnomAD 23 total heterozygotes (sampled from ~242458) for missense changes at this locus, no entry for this particular variant

Variant Evidence Fig 2C, Western blot: reduced TMEM199 expression in patient fibroblasts

FamilyAddInfo n/a

FamilyPMIDs n/a

PMID 22079513

Disease Idiopathic pulmonary fibrosis

Case# Subject 2, male, 8mo report, Hispanic

CasePresentingHPOs HP:0001276, HP:0000341, HP:0000294, HP:0000316, HP:0000286, HP:0000494, HP:0000664, HP:0008589, HP:0005989, HP:0001257 (Hypertonia, Narrow forehead, Low anterior hairline, Hypertelorism, Downslanted palpebral fissures, Epicanthus, Synophrys, Hypoplastic helices, Redundant neck skin, Spasticity)

HPOFreeText: Hypertonic(postnatal), bifrontal narrowing, low anterior hairline, mild hypertelorism, bilateral epicanthal folds, downslanted palpebral fissures, synophrys, mild hypoplastic helices, redundant nuchal skin, and spasticity of all four extremities with upper limbs being more affected than lower limbs (8 months old)

CaseNotHPOs HP:0002194, HP:0001252, HP:0012443, HP:0012372, HP:0000453, HP:0001627, HP:0000077, HP:0002650 (Gross motor delay, Hypotonia, Abnormality of the brain, Abnormal eye morphology, Choanal atresia, Congenital heart defects, Renal anomaly, Scoliosis)

CasePreviousTesting Screen for BRAF, CBL, HRAS, KRAS, MAP2K1, NRAS, PTPN11, RAF1, SCHOC2, and SOS1 was normal.

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

Variant NM_012102.3:c.248dup (p.Ser84ValfsTer4), de novo

ClinVar n/a

CAID CA658820860

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

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

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

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

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

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

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

ClinVar n/a

CAID CA338168785

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

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

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

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

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

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

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger in patient and parents

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

ClinVar n/a

CAID CA338168793

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

Family#PresentingHPOs HP:0001263, HP:0010864, HP:0002370, HP:0000664, HP:0000675, HP:0000545, HP:0001763, HP:0008763, HP:0000430, HP:0012471, HP:0000331, HP:0000303, HP:0000662, HP:0000529, HP:0011228

Absent or single-word speech, box-shaped face

FamilyNotHPOs

CountryOrigin Pakistani

Ethnicity

Race

Family#PreviousTesting None

Family#Method1

Family#Method2

Family#GenotypingMethod DNA samples from three affected (V-2, VI-2, VI-3) and two unaffected individuals (V-3, V-4), were genotyped using the Affymetrix Genome-Wide Human SNP 6.0 microarray.

homozygosity-by-descent (HBD) or autozygosity mapping and copy number variation (CNV) analysis was performed using dChip software.

direct Sanger sequencing of VPS13B was performed, based on homozygosity mapping results, for all 62 exons and splice junctions of VPS13B.

Potential candidate variants were further validated in Pakistani population controls through Sanger sequencing.

Affected 2

Unaffected 0

Segregations 1

PublishedLOD No

eLOD 0.6

AddSegregationInfo Pedigree in Figure 1. 5 affected and 3 unaffected individuals clinically determined.

ProbandLabel RQMR10_V-2

Variant NM_017890.4:c.6879delT(p.Phe2293Leufs*24)

ClinVar

CAID CA4824093

gnomAD 0.00003250 (South Asian)

FamilyAddInfo Complete biochemical testing in affected and unaffected. neurological, psychological, ophthalmological, skeletal, behavioral, dental examinations in affecteds. RQMR10_VI-2 underwent fundoscopic examination.

Case# Tun66275, Female, 20, Tunisia

CasePresentingHPOs HP:0002066, HP:0001260, HP:0001257

CaseNotHPOs HP:0001272

CaseMethod1 Exome

CaseMethod2 Sanger

Variant NM_005186.3:c.1534C>T(p.R512C)

CAID CA6093457

gnomAD 0.000008977

VariantEvidence none

CaseAddInfo in supplement

Case# Katagiri029, female, Japanese

CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod PCR of exons 4-11 of CNGA1

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs)

ClinVar 225315 link

gnomAD 0.001378 link

Case# Katagiri019, Female, Japanese

CasePresentingHPOs HP:0007987, HP:0007675, HP:0000551, HP:0007737

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod PCR of exons 4-11 of CNGA1

Variant NM_000087.3(CNGA1):c.265delC (p.Leu89Phefs) and novel "c.1429delG(p.V477YfsX17)"

ClinVar 1st 225315

CAID 2nd CA658820612

gnomAD 0.001378

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

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOSFreeText: no family history of SCD

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

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

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

ClinVarID: or CAID: CA401714383

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

AddCaseInfo: history of heart transplant, automatic implantable cardioverter defibrillator

PreviouslyPublished: no

VariantEvidence: none

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

CasePresentingHPOs:

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

CaseNOTHPOs:

CaseNOTHPOSFreeText: family history of HCM

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

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

Variant: c.432-1G>T

ClinVarID: or CAID: CA401717111

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

AddCaseInfo: history of ECG abnormalities

PreviouslyPublished: no

VariantEvidence: none

GroupPresentingHPOs: HP:0000768, HP:0002857, HP:0008454, HP:0001382, HP:0007957, HP:0000687, HP:0004630, HP:0002869, HP:0008807, HP:0002673, HP:0003311, HP:0003414, HP:0002656,

GroupNotHPOs:

GroupPreviousTesting:

GroupMethod1: single gene seq of GALNS exons and flanking intronic seqs

GroupMethod2: GALNS enzyme assa from leukocytes as prev described - range was 0 - 8 nmol/17hr/mg protein with ref range being 40 - 170s

GroupGenotypingMethod: single gene seq

NumberMales: 34

NumberFemales: 34

CountryOrigin: India

Ethnicity:

Race:

AgeRange: 1 - 26

TotalNumber: 68

FamilyInfo: Family blood samples were obtained and the authors state a 3 generation pedigree was constructed for each family but that data was not provided in the study.

NoFamily:

VariantCount: 40

NonVariant:

OtherVariant:

NonPatientCell: EFO:0005214

GOterm: GO:0016192

GeneAlteration: Undifferentiated N2A cells (murine neuroblastoma cell line) were infected with shRNAs to downregulate endogenous Rab39b expression by 45%.

FunctionalEvidence: N2A cells 4d after treatment with shRNA showed a change in morphology. Clumps of actin and reduced and/or altered membrane protrusions were observed. Rescue with WT RAB39B was able to restore the normal actin and cytoskeletal morphology, indicating that Rab39b may alter intracellular vesicular trafficking steps essential for membrane remodeling.

FAVariants:

NonPatientCell: CL:0002608

GOterm: GO:0016192

GeneAlteration: Rab39b expression was knocked down in mouse primary hippocampal neurons using shRNA

FunctionalEvidence: Expression of Rab39b was reduced by 40% as determined by RT-PCR. Morphological analysis showed significant alteration and the number of growth cones was decreased at each neurite terminal. Authors also show that RAB39B was localized to growth cones and could be involved in intracellular trafficking related to membrane recycling of Golgi-derived vesicles. Therefore RAB39B gene alterations can lead to impaired trafficking and lead to accumulation in membrane content and disorganized growth of growth cones.

FAVariants:

PMID: 34504088

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

genotype phenotype information for probands

Case#: Consequence 13 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.1358G>A (p.Arg453His)

ClinVar: 42838 https://www.ncbi.nlm.nih.gov/clinvar/variation/42838/

CAID: n/a

gnomAD: 0.0000 African https://gnomad.broadinstitute.org/variant/3-49167319-C-T

Case#: Consequence 22 Table 1 in Data Supplement (6 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.2722C>G (p.Leu908Val)

ClinVar: 14097 https://www.ncbi.nlm.nih.gov/clinvar/variation/14097/

CAID: n/a

gnomAD: 0.00006482 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23893316-G-C

Case#: Consequence 32 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.788T>C (p.Ile263Thr)

ClinVar: 43106 https://www.ncbi.nlm.nih.gov/clinvar/variation/43106/

CAID: n/a

gnomAD: 0.000008792 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23900635-A-G

Case#: Consequence 27 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.2609G>A (p.Arg870His)

ClinVar: 14120 https://www.ncbi.nlm.nih.gov/clinvar/variation/14120/

CAID: n/a

gnomAD: 0.00001549 European (non-Finnish) https://gnomad.broadinstitute.org/variant/14-23894048-C-T

Case#: Consequence 19 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.1491G>T (p.Glu497Asp)

ClinVar: 14124 https://www.ncbi.nlm.nih.gov/clinvar/variation/14124/

CAID: n/a

gnomAD: 0.0001984 Ashkenazi Jewish https://gnomad.broadinstitute.org/variant/14-23897796-C-A

Case#: Consequence 15 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.2167C>T (p.Arg723Cys)

ClinVar: 14095 https://www.ncbi.nlm.nih.gov/clinvar/variation/14095/

CAID: n/a

gnomAD: 0.00003266 South Asian https://gnomad.broadinstitute.org/variant/14-23895023-G-A

NonHumanModel: Mouse (Mus musculus)

GeneAlteration: Two approaches were used to create this model. The first imitated the slow fiber-specific expression of TPM3 by linking the coding region for αTm_slow(Met9Arg) to a human troponin I slow gene that drives expression specifically in these fibers via EcoRI-PstI digest and ligation into a linearized construct. The second, HSA–αTm_slow(Met9Arg), expressed the mutation in fast fibers by ligating a SmaI-BamHI cassette containing the intron and 3′-UTR of SV40 small t antigen directly downstream of the mutant cDNA sequence followed by blunt-end ligation of the HSA promoter into the EcoRV site upstream of the sequence before linearizing into a construct. These constructs were injected into fertilized eggs and screened by southern blot analysis to verify the successful insertion.

ModelPhenotype: HP:0003798, HP:0100303, HP:0100301, HP:0003557, HP:0001324, HP:0011807 (Nemaline bodies, Muscle fiber cytoplasmic bodies, Muscle fiber tubular aggregates, Increased variability in muscle fiber diameter, Muscle weakness, Type 1 muscle fiber atrophy)

ModelFreeText: Disorganized sarcomeres, Increased slow/fast oxidative fibers

HumanPhenotype: HP:0003798, HP:0003557, HP:0001324, HP:0011807 (Nemaline bodies, Increased variability in muscle fiber diameter, Muscle weakness, Type 1 muscle fiber atrophy)

HumanFreeText: Disorganized sarcomeres

ModelEvidence: The Met9Arg mouse models not only clearly recapitulate the phenotypes of nemaline/other myopathies but also provide evidence to suggest possible pathogenic mechanisms of the mutated allele in vivo. Mice expressing the mutated allele display nemaline rods and clear fiber-type disproportion, both of which are hallmarks for their respective diseases. They also displayed progressive muscle weakness starting around 5-6 months of age, a phenotype that matches the childhood-onset muscle weakness and other progressive symptoms common in TPM3-related congenital myopathy patients. Another classic phenotype, atrophy of Type I muscle fibers with a corresponding hypotrophy of Type II fibers was also present in the mice. This may be related to the increased number of slow/fast oxidative fibers in the mutant mice leading to the disruption of normal muscle fiber maturation. The mice also displayed some cytoplasmic bodies and tubular aggregates; these have been observed in varying functional studies and similar features have also been observed in humans.

ModelVariant: NM_152263.4(TPM3):c.26T>G (p.Met9Arg)

ClinVar: 12446 https://www.ncbi.nlm.nih.gov/clinvar/variation/12446/

Case# B12, Male, UK

CasePresentingHPOs HP:0010872

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# 39

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

HPOFreeText: axonal neuropathy

CaseNotHPOs n/a

NotHPOFreeText: n/a

CasePreviousTesting Screened for Inherited peripheral neuropathy variants, results negative.

CaseMethod1 WES

CaseMethod2 n/a

CaseGenotypingMethod n/a

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

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

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

CasePMIDs n/a

Case 5: HP:0001639, underwent myectomy, father died at age 63 of unknown cause, NM_005655.3:c.646A>G (p. Thr216Ala), gnomAD= 7.21e-5, Euro(NF)= 1.578e-4

Case 3: HP:0001639, underwent myectomy and ICD, two sons with neg echos, family history - mother died at 84, NM_005655.3:c.409G>A (p. Glu137Lys), gnomAD= 8.152e-6, Euro(Nf)=1.801e-5)

Family#PresentingHPOs HP:0001643

CountryOrigin Africa

Ethnicity Nonhispanic

Race Black

Family#Method1 WES

Family#Method2 Sanger

Family#GenotypingMethod PCR of 180k exons of 18,673 protein-coding genes, genome-wide linkage analysis was performed on the family along with WES on subjects III-2, IV-9, III-11 and IV-6

Affected 10

Unaffected 5

Segregations 8

PublishedLOD 2.57

AddSegregationInfo incomplete pentrance

ProbandLabel PDA-101:III-2, Female

Variant NM_001136239.3(PRDM6):c.1646G>A (p.Arg549Gln)

ClinVar 243049

VariantEvidence Functional in vitro characterization of PRDM6 p.Arg549Gln 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).

CaseF10:III-1: Italy

CasePresentingHPOs: N/A

CaseAddInfo: Proband for F10

CaseF5:II-2: Male, Italy

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

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

Family Label: Family of patient 13940

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

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

Affected: 6

Unaffected: 6

Segregations: 5

Proband label: 13940

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

CAID: CA288260

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

gnomAD: not found

Family#PresentingHPOs HP:0002047

CountryOrigin Italy

Ethnicity NonHispanic

Race White

Family#PreviousTesting no

Family#Method1 PCR

Affected 7

Unaffected 7

Segregations 5

PublishedLOD l.76

eLOD 1.5

ProbandLabel Pirone 2:1, male

Variant NM_000069.2(CACNA1S):c.4060A>T (p.Thr1354Ser)

ClinVar 161208 link

Patient Number: 1507278 Pt1

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

FamilyNotHPOs: HP:0002015

CountryOrigin: n/a

Ethnicity: n/a

Race: n/a

FamilyPreviousTesting: PLP1 mutation screening, PLP1 duplication/deletion analyses

FamilyGenotypingMethod: Nextra custom enrichment panel, trio-based WES

Affected: 1

Unaffected: 2

Segregations: consanguineous marriage

PublishedLOD: n/a

eLOD: n/a

AddSegregationInfo: consanguinity

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

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

CAID: CA658820948

gnomAD: n/a

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

additional phenotype info for this proband scored in PMID: 19336477

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

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

Case#: Caciotti_Patient1

Demographics:

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

CaseNotHPOs: HP:0008166

CasePreviousTesting:

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

CaseMethod2: CNV analysis by qPCR

CaseGenotypingMethod: Single gene seq by illumina

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

ClinVar: 93178 & 1048484

CAID: CA221057 & CA915941057

gnomAD: 16-88904133-C-T v2 &

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

CaseAddInfo:

CasePMIDs:

PMID: 11574891

Gene: TERC

Disease: Dyskeratosis congenita

MonDO: MONDO:0007485

InheritancePattern: AD

Notes: variant(s): NR_001566.1:n.408C>G, NR_001566.1:n.107_108delinsAG

Case: Bolino Proband 2 (Case 25 in PMID:10677858), female, reported at 5yo, symptom onset at 2yo

CasePresentingHPOs: HP:0001270, HP:0030319, HP:0008959, HP:0008994, HP:0009053, HP:0002522, HP:0003474, HP:0000218, HP:0001761, HP:0003447, HP:0012447 (motor delay, facial weakeness, distal upper limb muscle weakness, proximal lower limb muscle weakness, distal lower limb muscle weakness, lower limb areflexia, sensory impairment, high palate, pes cavus, axonal loss, abnormal myelination)

HPOsFreeText: walked at 17mo, tendon reflexes absent in lower limbs but present in upper limbs, sensory action potential absent in all nerves tested , CMAPs had small amplitude and temporal dispersion in upper limbs and were not detectable in lower limbs, EMG of tibialis anterior showed neurogenic features, presence of myelin loops and excessive outfolding, thick and irregular myelin sheaths

NotHPOs: HP:0003383 (onion bulb formation)

CountryOrigin: Saudi Arabia

PreviouslyPublished: 10677858

FamilyInfo: consanguineous family

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree

Variant 1: NM_003912.1:c.1480_1593del

ClinVar: 637472, https://www.ncbi.nlm.nih.gov/clinvar/variation/637472/

gnomAD: absent

Variant 2: NM_016156.5(MTMR2):c.826G>T (p.Glu276Ter)

ClinVar: 6233, https://www.ncbi.nlm.nih.gov/clinvar/variation/6233/

gnomAD: absent

ScoringNotes: both variants stated to be homozygous on same allele, assume variants in trans

Case: Bolino Proband 1 (proband 1945), male, reported at 4yo, symptom onset at 42mo

CasePresentingHPOs: HP:0001349, HP:0003701, HP:0001284, HP:0001288, HP:0003474, HP:0003693, HP:0003722, HP:0003391, HP:0001761, HP:0003383, HP:0012447 (bilateral facial weakness, proximal muscle weakness, areflexia, abnormal gait, sensory impairment, distal limb muscle atrophy, neck flexor weakness, Gower's sign, pes cavus, onion bulb formation, abnormal myelination)

HPOsFreeText: walked at 14mo, eyes reported to be normal, gait - bilateral steppage, pes equinovarus deformity of both feet, frequent falling, had normal early motor milestones, bilateral pes cavus with retraction of Achille's tendon, intellectually normal. Laboratory testing normal: full blood count, fasting blood glucose, serum electrolytes, creatine kinase, lactic acid, urinary organic acids, serum and urine carnitine, EEG, ECG, and liver echography, segmental demyelination in 92% of fibers, redundant loops of myelin sheath irregularly arrayed near axon, muscle biopsy of rectus femoris showed atrophic and angulated fibers in clusters and large type grouping, lipid accumulation

Median nerve conduction studies: compound motor action potential = 4.6uV, distal motor latency = 7.8msec, sensory action potential = 3.3uV, motor nerve conduction velocity = 17msec, sensory nerve conduction velocity = 18msec

Peroneal nerve conduction studies: compound motor action potential = 0.21uV, distal motor latency = 7.8msec, motor nerve conduction velocity = 14

Sural nerve conduction studies: sensory action potential = no response, sensory nerve conduction velocity = no response

CountryOrigin: Italy

FamilyInfo: consanguineous family, parents reported to be normal at clinical and electrophysiological exams

PreviouslyPublished: PMID:10673338, PMID:8817346, PMID: 8628474, PMID: 8017168

GenotypingMethod: RT-PCR of RNA from patient lymphoblastoid cell line, available family members analyzed and segregation of variant with disease confirmed in pedigree - PMID:8817346 - homozygosity mapping and haplotype sharing through microsatellite and linkage analysis

Variant: NM_016156.5(MTMR2):c.1276C>T (p.Gln426Ter) homozygous

ClinVar: 6231, https://www.ncbi.nlm.nih.gov/clinvar/variation/6231/

gnomAD: 0.000007085, https://gnomad.broadinstitute.org/variant/11-95578227-G-A

Lahat Family IV

Family#PresentingHPOs HP:0004758

CountryOrigin Israel

Ethnicity Arab

Race White

Family#Method1 whole genome

Family#Method2 PCR

Affected 3

Unaffected 4

Segregations 3, consanguineous (fig 1.)

PublishedLOD 8.24 combined

eLOD 1.70

ProbandLabel Lahat 2:2, female

Variant NM_001232.3(CASQ2):c.919G>C (p.Asp307His)

ClinVar 17610

gnomAD 0.00003249 link

FamilyPMIDs 11704930, links disease to a variant in CASQ2

Lahat Family I

Family#PresentingHPOs HP:0004758

CountryOrigin Israel

Ethnicity Arab

Race White

Family#Method1 whole genome

Family#Method2 PCR

Affected 3

Unaffected 5

Segregations 3, consanguineous (fig 1.)

PublishedLOD 8.24 combined

eLOD 1.82

ProbandLabel Lahat 2:6, female

Variant NM_001232.3(CASQ2):c.919G>C (p.Asp307His)

ClinVar 17610

gnomAD 0.00003249 link

FamilyPMIDs 11704930, links disease to a variant in CASQ2

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

DiseaseAssertion: MPS I Hurler

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

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

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod:

PreviouslyPublished: n/a

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

ClinVar: 550421

CAID: CA2802462

SupplementalData: n/a

CaseID 18

Zygosity Het for c.-129+9G>A, Het for c.357+1G>C

Phenotypes Iris grade 5 (aniridia or partial aniridia), HP:0000639, HP:0001104, HP:0001083, HP:0000482, HP:0000609

Segretation listed as sporadic, both parents unaffected and lack c.357+1G>C, father is het for c.-129+9G>A

Case# A13, male, 7

CasePresentingHPOs HP:0003124 Hypercholesterolemia

CasePreviousTesting The APOB domains, including amino acids 2955–3092 and amino acids 3303–3492, were analysed in the 600 molecularly undefined ADH cases by direct Sanger sequencing

CaseMethod1 as mentioned

CaseMethod2 as mentioned

CaseGenotypingMethod Exome sequencing

Variant NM_000384.2(APOB):c.9175C>T (p.Arg3059Cys)

ClinVar 69508

gnomAD 0.00003249 link

VariantEvidence Deficient LDL uptake (fig. 2)

Case#: KMP 8, female, 60 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic, LVOTO yes; LVEF 55-60%; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: 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

MultipleGeneVariants:

(1) SCN5A Variant:

Variant: NM_198056.2(SCN5A):c.3784G>A (p.Gly1262Ser)

ClinVar: 9399 https://www.ncbi.nlm.nih.gov/clinvar/variation/9399/

CAID: n/a

gnomAD: 0.0001307 South Asian https://gnomad.broadinstitute.org/variant/3-38607956-C-T

Case#: KMP 4, female, 69 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; NYHA II.-III.; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

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

CaseGenotypingMethod: Sanger sequencing;

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

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

CAID: n/a

gnomAD: absent

Case#: KMP 22, male, 21 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: symptomatic; LVEF 60%; ICD yes; ECG; echocardiography;

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO

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

CaseGenotypingMethod: Sanger sequencing;

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

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

CAID: n/a

gnomAD: absent

Case#: KMP 18, female, 71 yrs, East Slovakia

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

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

CaseGenotypingMethod: Sanger sequencing;

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

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

CAID: n/a

gnomAD: absent

Case# Subject 8, male, 10yo, European

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

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

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

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES confirmed with sanger

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

CAID CA658820843

gnomAD n/a

VariantEvidence n/a

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

CasePMIDs n/a

Case# Subject 7, male, 11yo, Dutch

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

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

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

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

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with sanger sequencing in patient and parents

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

ClinVar n/a

CAID CA571729

gnomAD 0.0001824(other), 0.00002032(total)

VariantEvidence n/a

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

CasePMIDs n/a

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

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

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

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

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmer with sanger

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

ClinVar n/a

CAID CA658820831

gnomAD n/a

VariantEvidence n/a

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

CasePMIDs n/a

list of some common phenoypes:

MONDO

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

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

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

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

CasePreviousTesting n/a

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES results confirmed with Sanger in pateint and parents

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

ClinVar n/a

CAID CA338168808

gnomAD n/a

VariantEvidence n/a

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

CasePMIDs n/a

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

Case3: Female, Italy, 7 yrs report

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

HPOsFreeText: Semi-solid diet

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

NotHPOsFreeText: Congenital myasthenic syndromes

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

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

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

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

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

gnomAD: Not in gnomAD

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

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

gnomAD: Not in gnomAD

Case2: Male, Italy, Birth onset

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

HPOsFreeText: Wheelchair dependent

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

NotHPOsFreeText: Congenital myasthenic syndromes

CaseAddInfo: Intermediate NM presentation, Parental segregation was confirmed

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

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

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

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

gnomAD: Not in gnomAD

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

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

gnomAD: Not in gnomAD

FamilyLabel Family 2

Family2PresentingHPOs HP:0000347, HP:0000157, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0030449

(Micrognathia,Tongue abnormality, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, therapeutic abortion)

HPOsFreeText Hydrocephalus/open-book, Occipitoschisis/keyhole, polymicrogyria, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

FamilyNotHPOs HP:0000202, HP:0001161, HP:0001627

(Oral cleft, Hand polydactyly, Congenital heart defect)

NotHPOsFreeText uterus duplex, hydranencephaly/ancephaly, leptomeningeal heterotopia, true alobar or semilobar holoprosencephaly

CountryOrigin Finland

Ethnicity n/a

Race n/a

Family2PreviousTesting n/a

ProbandLabel Case 2a, Female

Case2aPresentingHPOs HP:0001829

(Foot polydactyly)

HPOsFreeText 10cm crown-heel body length, 31g body weight, 4g brain weight, occipitotemporal hypoplasia, infratentorial hypoplasia, neuroepithelial rosettes. "anteriorly fused cerebral hemispheres are otherwise widely separated with a prominent cleft in the thalamic region. Midline structures are missing. The rhombencephalic flexure is prominent with an abnormal mesencephalic quadrigeminal region. A small cerebellum is seen with an open fourth ventricle below(Fig2). A disorganized cortex with many primitive neuroepithelial rosettes under the outer zone of the cortical plate is seen in the frontolateral cortex. The same rosette-rich region seen in MIB-1 staining shows very high proliferative activity in the inner luminal zones of the rosettes(Fig5)."

Case2aNotHPOs HP:0002101, HP:0007260, HP:0007165

(Defective lung lobation, Type II lissencephaly, Periventricular neuronal heterotopia)

NotHPOsFreeText Abnormal larynx/trachea

Case2aAddInfo induced abortion at 13.3wk gestational age

Case2b Male

Case2bPresentingHPOs HP:0002101, HP:0007260, HP:0007165

(Defective lung lobation, Type II lissencephaly, Periventricular neuronal heterotopia )

HPOsFreeText 20cm crown-heel body length, 210g body weight, 28g brain weight, abnormal larynx/trachea. "Microgyric nodular architecture with abundant gliovascular strands can be seen in the lateral parietal cortex."

Case2bNotHPOs HP:0001829

(Foot polydactyly)

NotHPOsFreeText Occipitotemporal hypoplasia, infratentorial hypoplasia, neuroepithelial rosettes,

Case2bAddInfo induced abortion at 17+6wk gestational age

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

ClinVar 1143

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

FamilyAddInfo n/a

FamilyPMIDs n/a

Case11 Female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001161, HP:0001627, HP:0000157, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0030449

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

HPOsFreeText Crown-heel body length 25cm, body weight 360g, brain weight 40g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0007165

(Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, neuroepithelial rosettes, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 20+5wk gestational age

CasePMIDs n/a

Case4 Female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001161, HP:0001829, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0030449

(Oral cleft, Micrognathia, Hand polydactyly, Foot polydactyly, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Therapeutic abortion)

HPOsFreeText Crown-heel body length 19cm, Body weight 160g, Brain weight 16g, abnormal larynx/trachea, Hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occititoschisis/keyhole, hypothalamic plate protrusion-hamartoma, steep rhombencephalic flexure with hypoplasia of posterior fossa contents, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001627, HP:0000157, HP:0007260, HP:0007165

(Congenital heart defect, Tongue abnormality, Type II lissencephaly, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, Hydranencephaly/anencephaly, leptomeningeal heterotopia, neuroepithelial rosettes, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 18+0wk gestational age

CasePMIDs n/a

Case15 Male, Finland

CasePresentingHPOs HP:0003826, HP:0000202, HP:0001161, HP:0001829, HP:0001627, HP:0002101, HP:0000238, HP:0001341, HP:0007370, HP:0010664, HP:0002126, HP:0007260, HP:0007165

(Stillbirth, Oral cleft, Micrognathia, Hand polydactyly, Foot polydactyly, Congenital heart defect, Defective lung lobation, Hydrocephalus, Olfactory lobe agenesis, Callosal agenesis, Fused thalami, Polymicrogyria, Type II lissencephaly, Periventricular neuronal heterotopia)

HPOsFreeText Crown-heel body length 45cm, body weight 2520g, brain weight 146g, polydactyly of toes with multiple extra toes, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000157

(Tongue abnormality)

NotHPOsFreeText Uterus duplex, 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 stillborn at 34+0wk gestational age

CasePMIDs n/a

Case10 Male, Finland

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

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

HPOsFreeText Crown-heel body length 25cm, body weight 250g, Brain weight 35g, abnormal larynx/trachea, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, leptomeningeal heterotopia, neuroepithelia rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0000202, HP:0001161, HP:0001627, HP:0000157, HP:0002444, HP:0007165

(Oral cleft, Hand polydactyly, Congenital heart defect, Tongue abnormality, Hypothalamic hamartoma, Periventricular neuronal heterotopia)

NotHPOsFreeText Uterus duplex, hydranencephaly/anencephaly, hypothalamic hamartoma/bulging, true alobar or semilobar holoprosencephaly, widely separated hemispheres without midline structures; only meningeal remnants cross the midline showing classical open-book appearance of HLS

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 19+5wk gestational age

CasePMIDs n/a

Case1 female, Finland

CasePresentingHPOs HP:0000202, HP:0000347, HP:0001341, HP:0000238, HP:0002126, HP:0007165, HP:0030449

(Oral Cleft, Micrognathia, Olfactory lobe agenesis, Hydrocephalus, Polymicrogyria, Periventricular neuronal heterotopia, Therapeutic abortion)

HPOsFreeText crown-heel length: 8cm, weight: 9g, hydrocephalus/open-book, occipitotemporal hypoplasia, infratentorial hypoplasia, occipitoschisis/keyhole, neuroepithelial rosettes, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

CaseNotHPOs HP:0001161, HP:0001829, HP:0001627, HP:0000157, HP:0002101, HP:0007370, HP:0010664, HP:0002444, HP:0007260

(Hand polydactyly, Foot polydactyly, Congenital heart defect, Tongue abnormality, Defective lung lobation, Callosal agenesis, Fused thalami, Hypothalamic hamartoma, Type II lissencephaly)

NotHPOsFreeText abnormal larynx/trachea, uterus duplex, hydranencephaly/anencephaly, hypothalamic bulging, leptomeningeal heterotopia, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 12+1wk gestational age

CasePMIDs n/a

Korean stroke patients who were carriers of COQ5 rs10849757 were more associated with statin related myotoxicity risk than wild-type homozygote carriers (GG) (9.7% vs. 3.9%, p = 0.024). Only group demographics provided rather than individual phenotype/genotype information

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

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

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

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

CaseNOTHPOSFreeText: scrotal masses

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

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

Variant: G427S homozygous

ClinVarID: or CAID: 563/CA114349

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

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

PreviouslyPublished: PMID: 18410979

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

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

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

CasePresentingHPOsFreeText: dilated scleral vessels

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

CaseNOTHPOSFreeText:

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

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

Variant: G437R homozygous

ClinVarID: or CAID: 565/CA114352

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

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

PreviouslyPublished: PMID: 18410979

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

Case# A3054-21, Macedonian, Male, 5yr age of onset

CasePresentingHPOs HP:0001919, HP:0000121, HP:0000074

CasePreviousTesting 30 genes previously linked to nephrolithiasis were screened by exon sequencing in these individuals, but no causative mutations were detected

CaseMethod1 NGS

CaseGenotypingMethod list of 18 hypothetical candidate genes and performed exon amplification with consecutive next-generation sequencing in a multicenter cohort of 348 individuals with nephrolithiasis or isolated nephrocalcinosis

Variant NM_134425.2(SLC26A1):c.554C>T (p.Thr185Met), NM_022042.3(SLC26A1):c.1073C>T (p.Ser358Leu)

ClinVar 242374, 242375

gnomAD 0.0004342, 0.0005655

VariantEvidence Immunofluorescence of SLC26A1 protein, when overexpressed in HEK293 cells, showed that p.Thr185Met causes protein to fail to reach plasma membrane (Figure 2). Monitoring of intracellular pH showed that p.Thr185Met has severely reduced activity (Figure 4). PCR of slc26a1 transcript in H293K cells showed no change in amount of transcript suggesting that the low p.Ser363Leu band levels in the immunoblot (Figure 3) were due to low portein stability.

Case# B641-12, "European," Male

CasePresentingHPOs HP:0000787

CaseNotHPOs HP:0003159

CasePreviousTesting 30 genes previously linked to nephrolithiasis were screened by exon sequencing in these individuals, but no causative mutations were detected

CaseMethod1 NGS

CaseGenotypingMethod list of 18 hypothetical candidate genes and performed exon amplification with consecutive next-generation sequencing in a multicenter cohort of 348 individuals with nephrolithiasis or isolated nephrocalcinosis

Variant NM_134425.2(SLC26A1):c.166G>A (p.Ala56Thr)

ClinVar 242376

gnomAD 0.0005655

VariantEvidence Monitoring of intracellular pH in transfected HEK293 demonstrated that p.Ala56Thr had reduced anion exchange activity. (Figure 4)

CaseAddInfo homozygous, consanguineous parents

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

NonHumanModel: Niu_Mouse

GeneAlteration: Transcription activator like effector nuclease (TALEN) - mediated strategy was used to target exon 1 of RAB39B to generate the knockout mice in the C57BL/6J background. A mouse line with a "GT" deletion at nucleotide 106-107 that caused a frameshift and early truncation of RAB39B was obtained. Authors confirmed absence of RAB39B loss of fucntion.

ModelPhenotype: Learning and memory deficits

HumanPhenotype: HP:0001249

ModelEvidence: 2-mo hemizygous male knock-out (KO) mice showed behavioral alterations compared to WT mice. KO mice showed reduced anxiety, impaired recognition memory, impaired short-term working memory, impaired spatial memory, impaired social novelty recognition, compromised motor skill learning, but motor ability was not affected. Authors indicate that impaired learning and memory was associated with altered synaptic plasticity.

ModelVariant:

WhereInPaper:

The evidence is scored minimal points as the phenotype recapitulated aligns with the human ID phenotype; however, the model provides no evidence of Parkinson disease phenotype. (0.5)

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

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

ClinVar 224316

CAID CA2520544

gnomAD 0.0003508(Latino), 0.0001121(Total)

RescuePatientCell CL:0000057

GeneAlteration NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala) and/or NM_017819.3(TRMT10C):c.542G>T (p.Arg181Leu)

RescuePhenotype defective oxidative phosphorylation and tRNA 5' processing affecting high energy demand tissues: HP:0001508 (Failure to thrive)

RescueMethod Fibroblasts transfected with lentiviral vector containing single copy of WT TRMT10C.

RescueEvidence Transfected patient cells had increased MRPP1 expression, restored mitochondrial translation, normalized levels of respiratory chain complexes and mt-tRNA precursors which rescues the reduced cellular oxidative phosphorylation and slowed growth. 21857155 demonstrates both the restriction of translation and reduction of the rate of oxidative phosphorylation during MRPP1 knockdown in HeLa cells (Fig 5). Those result corroborate the gap between reduced MRPP1 expression and reduction in translation of oxidative phosphorylation machinery.

RescueVariants n/a

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

Family#: RW kindred

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

CountryOrigin: Lebanon (Christian)

Family#Method1: PCR

Family#Method2: Sanger sequencing

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

Affected: 2 homozygotes, 14 heterozygotes

Unaffected: 20 (i.e. homozygous normal)

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

ProbandLabel: Subject III:6

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

ClinVar: N/A

CAID: CA053659

gnomAD: 0.00001759 (European non-Finnish)

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