NonPatientCell: EFO:0001182 (HEK293 Cells)

GeneFunction: GO:0008233 (Peptidase activity)

GeneAlteration: HEK293 cells were grown and 8 missense mutations were identified and generated by PCR-mutagenesis. The human mutant cDNAs were transfected into the cells using the calcuim-phosphate coprecipitation method and examined.

FunctionalEvidence: When HEK293 cells were transfected with wild-type and mutant human cDNA for PHEX, the resulting cells were subject to immunoblotting to determine the protein levels in both the cell lysate and the media of cells. All the variants and the wild-type showed presence in the lysate at various levels, but C85R, G579R, G579V, S711R, and A720T were all devoid of any secreted protein in the media. Ananlysis of these cells also showed possible rescue by growing transfected cells at 26 C, thus glycosylating and maturing the proteins. The endopeptidase activity of the wild-type and variants were also compared, with D237G and Y317F mutant proteins exhibiting 50–60% of wild-type activity; E581V and S711R also displayed nearly undetectable activity. This displayed that the disease causing mechanism could be related to loss of function of peptidase activity or cellular trafficking. Evidence is found under "Results".

FAVariant1: NM_000444.5:c.253T>C (p.Cys85Arg)

ClinVar: 438549 https://www.ncbi.nlm.nih.gov/clinvar/variation/438549/

FAVariant2: NM_000444.5:c.1735G>A (p.Gly579Arg)

ClinVar: 226119 https://www.ncbi.nlm.nih.gov/clinvar/variation/226119/

FAVariant3: NM_000444.5:c.1736G>T (p.Gly579Val)

ClinVar: 372777 https://www.ncbi.nlm.nih.gov/clinvar/variation/372777/

FAVariant4: NM_000444.5:c.2131A>C (p.Ser711Arg)

CAID: CA412575294 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA412575294

FAVariant5: NM_000444.5:c.2158G>A (p.Ala720Thr)

CAID: CA412575364 https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA412575364

This variant was mentioned as being previously published (PMID: 12559846). Structural changes for this variant were analyzed by calculating RMSD and predicted this variant to result in a severe phenotype. However, this type of prediction is not used by the LD VCEP.

PMID: 18241071

Gene: PAX6

Variant NM_001368894.2:c.-128-2del

Disease: Ocular dysgenesis

InheritancePattern: AD

Disease PAX6-related ocular dysgenesis MONDO:0800183

Case 1: HP:0001639 KLF10 no family history NM_005655.3:c.34G>A (p.Ala 12Thr) gnomAD= 4.108e-6

Case 2: HP:0001639, parents and siblings had neg echos, no family history, HCM was NOT late onset (diagnosed at 15), myectomy performed, NM_005655.3:c.80T>C (p. Met 27Thr), gnomAD=7.91e-5, euro(Nf)= 1.344e-4

Case 6: HP:0001639, HP:0001635, HP:0006510, died at 76 of heart failure and COPD, NM_005655.3:c.674G>C (p. Ser225Asp), gnomAD= 1.118e-3 Euro (NF)= (1.16e-2)

PMID: 28851564

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Unable to annotate on article.

Case#: Konstantinidis Case 2

DiseaseAssertion: optic atrophy

FamilyInfo: none provided

CasePresentingHPOs: none, tests performed on blastocyst

CaseHPOFreeText:

CaseNotHPOs: none

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.182A > G

ClinVar: 511815

CAID: CA2758946

SupplementalData: n/a

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

DiseaseAssertion: OA plus

FamilyInfo: Pedigree (Fig 1) shows 6 segregations

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

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

CaseNotHPOs: HP:0001627, HP:0031983

CaseNotHPOFreeText:

PreviouslyPublished: n/a

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

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

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

ClinVar: 30461

CAID: CA10575554

SupplementalData:

Case: 8

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

(1) LAMA4 Variant: c.2593C>G (unknown HGVS descriptor)

ClinVarID: unknown

gnomAD: unknown

(2) MYH7 Variant: NM_000257.4:c.3158G>A

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.0000601 European (Finnish): 0.0006368

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

Case: 2

DiseaseAssertion: hypertrophic cardiomyopathy, Left ventricular hypertrophy

FamilyInfo: Finnish, no family info

CasePresentingHPOs: HP:0001639, HP:0001712

"hypertrophic cardiomyopathy, Left ventricular hypertrophy"

CaseHPOFreeRext:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: 24 h Holter registration and bicycle ergometer test performed in majority of patients. Cardiac magnetic resonance imaging was performed to verify the diagnosis of HCM

GenotypingMethod: Targeted next-generation sequencing of exons, UTRs and 10 bp flanking regions of 59 cardiomyopathy associated genes, filtered variants confirmed by Sanger sequencing

MultipleGeneVariants:

(1) MYH7 Variant: NM_000257.4:c.3158G>A

ClinVarID: 155814

gnomAD: http://gnomad.broadinstitute.org/variant/14-23891476-C-T

Total Allele Frequency: 0.00006010 European Finnish: 0.0006368

(2) MYBPC3 Variant: NM_000256.3:c.440C>T

ClinVarID: 181035

gnomAD: http://gnomad.broadinstitute.org/variant/11-47371630-G-A

Total Allele Frequency: 0.0005896 European (Finnish): 0.005563

(3) MYOZ2 Variant: NM_016599.4:c.738A>G

ClinVarID: 30509

gnomAD: http://gnomad.broadinstitute.org/variant/4-120107298-A-G

Total Allele Frequency: 0.0023 European (Finnish): 0.02188

(4) PSEN2 Variant: NM_012486.2:c.211C>T

ClinVarID: 192130

gnomAD: http://gnomad.broadinstitute.org/variant/1-227071475-C-T

Total Allele Frequency: 0.003711 European (Finnish): 0.01791

(5) SCN5A Variant: NM_000335.4:c.1715C>A

ClinVarID: 67683

gnomAD: http://gnomad.broadinstitute.org/variant/3-38645378-G-T

Total Allele Frequency: 0.005175 European (Finnish): 0.03855

PreviouslyPublished:

SupplementalData: Table S3: list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF <1%) detected in each patient.

annotating here since this is a PDF

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

DiseaseAssertion: Hurler

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: mental delay. height=70cm

CaseNotHPOs: HP:0002240

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

annotating here since this is a PDF

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

DiseaseAssertion: Hurler/Scheie

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

CasePresentingHPOs: HP:0001433

CaseHPOFreeText: height=90cm (-1.2SD)

CaseNotHPOs:

CaseNotHPOFreeText: mental delay. cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5; R89Q

ClinVar: 11921; 11922

CAID: CA256123; CA256124

SupplementalData: n/a

annotating here since this is a PDF

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

DiseaseAssertion: Hurler

FamilyInfo: consanguinity

CasePresentingHPOs: HP:0002240

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

CaseNotHPOs:

CaseNotHPOFreeText: cardiac involvement

PreviouslyPublished: n/a

Variant: 704ins5/704ins homozygous

ClinVar: 11921

CAID: CA256123

SupplementalData: n/a

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

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: no LVOTO; no ICD

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

CaseGenotypingMethod: Sanger sequencing

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

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

CAID: n/a

gnomAD: absent

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

DiseaseAssertion: HCM

FamilyInfo: n/a

CasePresentingHPOs: n/a

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

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

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

CaseGenotypingMethod: Sanger sequencing;

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

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

CAID: n/a

gnomAD: absent

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

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

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

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

CAID: CA350723588

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

Case#: P937, F, Italian

CasePresentingHPOs: HP:0007354

CaseGenotypingMethod: Sanger sequencing

Variant: c.19C>A p.Val7Ile

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

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

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

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

CaseNotHPOs: HP:0100543

CaseGenotypingMethod: Sanger sequencing

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

CAID: CA2018007638

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

NonHumanModel Mus Musculus

GeneAlteration The knock-in strain was generated by homologous recombination of the targeting vector with 129Sv/J embryonic stem cells genome. A 450-bp DNA segment encompassing 5′ UTR and exon 1 of the CASQ2 was used to screen RPCI-21 PAC mouse genomic library. Positive clones were sequenced to define the structure of an 8.5-Kb region encompassing promoter, exon 1, and part of intron 1 of mouse CASQ2. This region was cloned in 3 parts and assembled into the targeting vector pFlrt (supplemental Figure I). The linearized targeting vector was electroporated into 129Sv/J embryonic stem cells. The clone selected with G418 and gancyclovir was injected into C57BL/6NCrL blastocyts and transferred to pseudopregnant CD-1 females. Genotype was determined by sequencing of DNA extracted from tail biopsy specimens (DNasy Tissue Kit, Qiagen).

ModelPhenotype HP:0004758

HumanPhenotype HP:0004758

ModelEvidence Fig. 1 ECG during stimuli shows VT in only the mutant mice

ModelVariant NM_001232.3(CASQ2):c.97C>T (p.Arg33Ter), 41043 link

Proband III:15, 47 yr old male, Dx = 37 yrs

HP:0001639, HP:0001681

HCM, chest tightness (angina)

Variant: NM_016599.4(MYOZ2):c.505A>C (p.L169G)

Not in ClinVar or EXAC

Variant NM_005186.3(CAPN1):c.407delC (p.Pro136Argfs), NM_001198868.1(CAPN1):c.1605+5G>A

ClinVar 225767, 225768

gnomAD none, 0.0003171

Case# FamilyC:IV-13, 33 AoO, Female, USA

CasePresentingHPOs HP:0002064, HP:0001258, HP:0002355

CaseMethod1 WES

CaseMethod2 Sanger

Variant NM_005186.3(CAPN1):c.407delC (p.Pro136Argfs), NM_001198868.1(CAPN1):c.1605+5G>A

ClinVar 225767, 225768

gnomAD none, 0.0003171

CaseAddInfo nonconsanguineous family

Family#PresentingHPOs HP:0001258, HP:0002460, HP:0007067, HP:0002395

CountryOrigin Morocco

Race White

Family#Method1 WES

Family#Method2 Sanger

Affected 4

Unaffected 3

Segregations 4

eLOD 1.93

AddSegregationInfo consanguineous

ProbandLabel FamilyB:IV-1 age of onset 35, Male

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

ClinVar 225766

FamilyAddInfo Fig 1

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

DiseaseAssertion: Hurler/Scheie

FamilyInfo:

CasePresentingHPOs:

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

CaseNotHPOs:

CaseNotHPOFreeText: mongolian macula, hernia, airway obstruction

PreviouslyPublished:

Variant: p.A79V; c.1225dupG

ClinVar: 1458769;

CAID: CA356987

SupplementalData:

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

DiseaseAssertion: Hurler

FamilyInfo:

CasePresentingHPOs:

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

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished:

Variant: p.A79V; 668insGCG

ClinVar: 1458769;

CAID: CA356987

SupplementalData:

FamilyLabel: Van Driest Family

Family#PresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy)

FamilyNotHPOs:

CountryOrigin:

Ethnicity:

Race:

Family#PreviousTesting: Three highly polymorphic markers for each of 9 known HC genes (MYH7, TNNT2, TNNI, TPM1, MYL3, MYL2, MBPC, ACTC, and PRKAG2) were PCR-amplified for haplotype analysis. Only 3 candidate genes, MYL3, TNNT2, and TPM1, were shared by proband, affected siblings, and father.

Family#Method1: (other) PCR amplification of all protein-coding exons and splice junctions of the 3 candidate genes from genomic DNA was analyzed using DHPLC (denaturing high-performance liquid chromatography).

Family#Method2: Cycle sequencing was performed on all DHPLC amplicons with abnormal elution profiles (exon 5 of TPM1).

Family#GenotypingMethod: DHPLC screening followed by cycle sequencing of TPM1 exon 5.

Affected: 4

Unaffected:

Segregations: 3 (Figure 1)

PublishedLOD: N/A

eLOD: N/A; < 4 segregations

AddSegregationInfo:

ProbandLabel: III-1

Variant: NM_001018005.2(TPM1):c.554T>G (p.Leu185Arg)

ClinVar: 31881

CAID: CA019057

gnomAD: 15-63060930-T-G has no data in gnomAD v4.0.0

FamilyAddInfo: TPM1 variant reported as c.T610G (p.L185R), using coding positions relative to GeneBank accession M19713.1?

FamilyPMIDs:

Case#: III-1

CasePresentingHPOs: HP:0001639 (hypertrophic cardiomyopathy); HP:0001645 (sudden cardiac death)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: None for the proband

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: DNA extracted from paraffin-embedded spleen tissue, taken at autopsy, was subjected to PCR-amplification of TPM1 exon 5 followed by cycle sequencing to confirm presence of the familial TPM1 variant.

Variant: NM_001018005.2(TPM1):c.554T>G (p.Leu185Arg)

ClinVar: 31881

CAID: CA019057

gnomAD: 15-63060930-T-G has no data in gnomAD v4.0.0

VariantEvidence: Chang, et al. 2005 (PMID:16043485) demonstrated in ATPase activity assays that myofibrils reconstituted with L185R mutant tropomyosin had an increased sensitivity to calcium compared to wild-type tropomyosin-reconstituted myofibrils.

CaseAddInfo: No other genes were screened for mutations in this proband.

CasePMIDs:

PMID: 30334364

Variant NM_000280.5:c.1123C>A (p.Pro375Thr)

Gene: PAX6

Disease: Ocular dysgenesis

InheritancePattern: AD

Case# Pt1, female, 16yo diagnosis, French

CasePresentingHPOs HP:0001433, HP:0001263, HP:0001252, HP:0001395, HP:0000744, HP:0000718, HP:0000713, HP:0001397, HP:0003651, HP:0012465, HP:0001999, HP:0003155, HP:0003124, HP:0010837, HP:0011967, HP:0012852 (Hepatosplenomgaly, Psychomotor delay, Hypotonia, Hepatic fibrosis, Low tolerance to frustration, Aggressiveness, Agitation, Hepatic steatosis, Foamy histiocytes, Increased liver iron, Dysmorphic facies, Elevated alkaline phosphatase, High cholesterol, Decreased ceruloplasmin, Copper deficiency, Hepatic bridging fibrosis)

HPOsFreeText Hepatospenomegaly and cholestasis(spontaneously resolved) (neonate); Elevated liver enzymes, psychomotor delay, hypotonia(6mo); liver cytolysis, portal-to-portal bridging fibrosis without regenerative nodules, fatty hepatocytes, foamy histiocytes, and iron overload(4yo); behavioral issues, dysmorphic features, elevated relative exchangeable and urinary copper and other metabolic abnormalities(13yo);enlarged portal tracts and liver tissue abnormalities (Fig1)

CaseNotHPOs HP:0200032 (Kayser-Fleischer ring)

CasePreviousTesting Negative for NPC and Wilson disease(ATP7B variants) as well as TMEM199 variants. Metabolic results: ASAT 56 U/L, ALAT 45 U/L [N < 40 U/L]; ALP 196 U/L [N < 119 U/L], cholesterol 5.50 mmol/L [N < 5.20 mmol/L], ceruloplasmin 0.55 μmol/L [N = 2–4.5 μmol/L], total copper 5.44 μmol/L [N = 12.5–22.5 μmol/L], y-gutamyltransferase, bilirubin, CK, glucose, lactic acid, plasma amino acids, urinary organic acids, and lysosomal acid lipase were normal, Bis(Monoacylglycero)Phosphate was also elevated.

CaseMethod1 Direct sequencing

CaseMethod2 n/a

CaseGenotypingMethod Sequenced CCDC115 and TMEM199 in patients and parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.19C>T(p.Arg7Ter)

ClinVar (1) 218967 (2) n/a

CAID (2) CA1871401

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) 0.00002691(European (Non-Finnish)), 0.00001220(Total)

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt2, male, 20yo report, French

CasePresentingHPOs HP:0200123, HP:0003155, HP:0003236, HP:0003124, HP:0003141, HP:0010837, HP:0006580, HP:0012852, HP:0025321 (Chronic Hepatitis, Elevated alkaline phosphatase, Elevated CK, High cholesterol, Elevated LDL cholesterol, Decreased ceruloplasmin, Portal fibrosis, Hepatic bridging fibrosis, Liver copper accumulation)

CaseNotHPOs HP:0002240, HP:0001744, HP:0001999, HP:0200032 (Hepatomegaly, Splenomegaly, Dysmorphic facies, Kayser-Fleischer ring)

CasePreviousTesting Negative for NPC and Wilson disease(ATP7B variants) as well as TMEM199 variants. Metabolic workup: ALAT 154 U/L, ASAT 137 U/L [N < 40 U/L] for >6 months, GGT was normal, ALP 218 U/L [N < 119 U/L], CK 519 U/L [N < 190 U/L], cholesterol 8.16 mmol/L [N < 5.7 mmol/L], ceruloplasmin 0.54 μmol/L [N = 2–4.5 μmol/L], normal urinary copper, REC 19% [N = 3.0–8.1%], liver copper 2.47 μmol/g, [N = 0.3–0.9 μmol/g]

CaseMethod1 Direct sequencing

CaseMethod2 n/a

CaseGenotypingMethod Sequenced CCDC115 and TMEM199 in patients and parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.38T>C(p.Leu13Pro)

ClinVar (1) 218967 (2) n/a

CAID (2) CA348488009

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) n/a

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

Case# Pt3, male, 16yo diagnosis, French

CasePresentingHPOs HP:0009062, HP:0001433, HP:0001396, HP:0003124, HP:0012852, HP:0001414, HP:0011924, HP:0001409, HP:0001394, HP:0011343, HP:0002342, HP:0003236, HP:0001315, HP:0010837, HP:0010836 (Infantile axial hypotonia, Hepatosplenomegaly, Cholestasis, High cholesterol, Hepatic bridging fibrosis, Microvesicular hepatic steatosis, Mitochondrial complex III deficiency, Portal hypertension, Cirrhosis, Moderate global developmental delay, Moderate ID, Elevated CK, Absent deep tendon reflexes Decreased ceruloplasmin, Abnormal copper homeostasis)

HPOsFreeText Hepatosplenomegaly and choleostasis reported at birth. Enlarged portal tracts, focal portal inflammation, loss of interlobular ducts in 1/3 of portal tracts and proliferation of bile ductules, lobular steatosis

CaseNotHPOs HP:0003200 (Ragged red fibers)

NotHPOsFreeText foamy hepatoocytes, bile plug

CasePreviousTesting Negative for NPC, Gaucher and Wilson disease(ATP7B variants) as well as TMEM199 variants. Excluded acid lipase deficiency. Negative for disease causing variants in any known genes involved in mitochondrial metabolism. Ruled out type IV glycogen storage disease. Metabolic results: cholesterol 9.92 mmol/L [N < 5.2 mmol/L], ceruloplasmin 0.09 g/L [N = 0.2–0.5 g/L], REC 18% [N = 3.0–8.1%], normal serum(4.16 μmol/L) and exchangeable copper(0.75 μmol/L). Glycogen and cytochrome oxidases were normal.

CaseMethod1 Exome sequencing

CaseMethod2 n/a

CaseGenotypingMethod Exome sequenced patient DNA, direct sequenced CCDC115 and TMEM199 in parents

Variant (1) NM_032357.3(CCDC115):c.92T>C (p.Leu31Ser) (2) NM_032357.3:c.19C>T(p.Arg7Ter)

ClinVar (1) 218967 (2) n/a

CAID (2) CA1871401

gnomAD (1) 0.00002384(European (Non-Finnish)), 0.00001086(Total) (2) 0.00002691(European (Non-Finnish)), 0.00001220(Total)

VariantEvidence see note on Fig 2

CaseAddInfo nonconsanguineous

CasePMIDs 26833332

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

gnomAD: absent

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

gnomAD: absent

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

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

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

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

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

gnomAD: absent

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

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

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

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

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

gnomAD: absent

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

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

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

DiseaseAssertion: HCM

FamilyInfo: N/A

CasePresentingHPOs: N/A

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

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

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

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

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

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

CAID: n/a

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

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

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

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

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

CaseNOTHPOs: HP:0000365, HP:0001250

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

CaseGenotypingMethod: WES

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

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

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

CA ID: CA658820925

de novo

gnomAD: not present

AddCaseInfo:

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

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

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

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

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

NotHPOFreeText: Ventillator dependence

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

CaseMethod1 WES

CaseMethod2 Sanger

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

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

ClinVar n/a

CAID CA357822100

gnomAD n/a

VariantEvidence n/a

CaseAddInfo consanguinity

CasePMIDs n/a

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

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

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

CaseNotHPOs HP:0002376 (Developmental regression)

NotHPOFreeText: Ventilator dependence

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

CaseMethod1 WES

CaseMethod2 Sanger

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

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

ClinVar 183338

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

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

CaseAddInfo Consanguinity

CasePMIDs 25558065

PMID: 31140649

Gene: HEXB

Disease: Sandhoff Disease

MonDO: MONDO:0010006

FamilyLabel Family 6

Family6PresentingHPOs HP:0000202, HP:0000347, HP:0001161, HP:0000157, HP:0002101, HP:0002324, HP:0030449

(Oral cleft, Micrognathia, Hand polydactyly, Tongue abnormality, Defective lobation of lungs, Hydranencephaly, Therapeutic abortion)

HPOsFreeText abnormal larynx/trachea, basal occipitoschisis/keyhole, absent developed and identifiable mamillary bodies, absent anterior commissure, difficult to identify nucleus dentatus

FamilyNotHPOs n/a

NotHPOsFreeText true alobar or semilobar holoprosencephaly

CountryOrigin Finland

Ethnicity n/a

Race n/a

Family6PreviousTesting n/a

ProbandLabel Case 6a, Male

Case6aPresentingHPOs HP:0001627

(Congenital heart defect)

HPOsFreeText Crown-heel body length 17.5cm, body weight 149g

Case6aNotHPOs n/a

NotHPOsFreeText Uterus duplex

Case6aAddInfo induced abortion at 18+2wk gestational age

Case6b Female

Case6bPresentingHPOs HP:0001829, HP:0010066

(Foot polydactyly, Duplicated hallux)

HPOsFreeText crown-heel body length 22cm, body weight 170g, uterus duplex, "absence of the dorsal arch of the first and second cervical vertebrae and the pituitary"

Case6bNotHPOs n/a

Case6bAddInfo induced abortion at 19+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

Case9 Male, Finland

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

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

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

CaseNotHPOs HP:0001161

(Hand polydactyly)

NotHPOsFreeText Uterus duplex, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 19+5wk gestational age

CasePMIDs n/a

Case14 Female, Finland

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

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

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

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

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

NotHPOsFreeText hydranencephaly/anencephaly, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

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

CasePMIDs n/a

Case8 Male, Finland

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

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

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

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

(Hand polydactyly, Tongue abnormality, Periventricular neuronal heterotopia)

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

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 19+0wk gestational age

CasePMIDs n/a

Case3 Female, Finland

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

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

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

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

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

NotHPOsFreeText Uterus duplex, true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 15+6wk gestational age

CasePMIDs n/a

Case18 Male, Finland

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

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

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

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

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

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

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo stillbirth, 36+6wk gestational age

CasePMIDs n/a

Case5 Male, Finland

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

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

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

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

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

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

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo induced abortion at 18+1wk gestational age

CasePMIDs n/a

Case13 Female, 6day old death, Finland

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

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

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

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

(Oral cleft, Foot polydactyly, Congenital heart defect)

NotHPOsFreeText true alobar or semilobar holoprosencephaly

CasePreviousTesting n/a

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

ClinVar 1143

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

CaseAddInfo 33+5wk gestational age

CasePMIDs n/a

Case#: GC20578

PresentingHPOs:HP:0000666, HP:0000486, HP:0000540, HP:0001103

PresentingHPOsText: Horizontal nystagmus, strabismus, difficulties with near vision, bilateral central macular disturbance.

CaseNotHPOs: HP:0007642, HP:0031605

CaseNotHPOsText: No night blindness, no fundus abnormalities

CasePreviousTesting: "Previous extensive genetic testing results were negative"

CaseGenotypingMethod1: WES

CaseGenotypingMethod1: Confirmed by bidirectional Sanger sequencing.

Variant: NM_002075.3: c.124C>T (p.Arg42Ter), homozygous

ClinVar: Not in ClinVar

CAID: CA6417419

gnomAD: Pop max MAF 0.00006706 (Latino). No homozygotes.

gnomAD

Case2: Female, Austria, 18 yrs report

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

HPOsFreeText: 3/3/5 Apgar score

CaseNotHPOs: HP:0002015 (Swallowing difficulties)

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

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

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

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

gnomAD: Not in gnomAD

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

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

gnomAD: Not in gnomAD

Case3: Male, Germany, 20 yrs report

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

HPOsFreeText: 7/8/9 Apgar score

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

NotHPOsFreeText: N/A

CaseAddInfo: N/A

CasePreviousTesting: N/A

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

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

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

gnomAD: Not in gnomAD

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

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

gnomAD: Not in gnomAD

PMID: 32428220

Gene: GDAP2

HGNCID: HGNC:18010

NonPatientCell UBERON:0005424

GOterm GO:0042802

GeneAlteration shRNAs cloned into pCAG-mir30 vector that contained a puromycin resistance gene.

FunctionalEvidence electron microscopy of RPE in 1-2 yo mice showed 37-48% reduced phagocytosis in mutants. (fig. 1) Assayed cryosection of mouse RPE showed mislocalization of adhesion/phagocytosis markers in RPE (fig. 4)

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

Case 1: Family A: AII-1, female

Born at 37 weeks, consanguineous family, APGAR = 9, tachypnea developed shortly after birth. At 20 weeks, skeletal abnormalities and kidney and liver cysts were detected. Died at 7 weeks from renal insufficiency.

HPO Terms: HP:0002652, HP:0001999, HP:0002789, HP:0005562, HP:0001407, HP:0009826, HP:0000926, HP:0001156, HP:0000085, HP:0000083, HP:0002079, HP:0002119, HP:0030747, HP:0011839

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

Genotyping Method: WES, CNV performed on WES data, EXTL3 fibroblast localization tested and compared to non-affected controls using immunocytochemistry

Variant: p.Arg513Cys, g.28575113, c.1537C>T

ClinVar ID: n/a

gnomAD: http://gnomad.broadinstitute.org/variant/8-28575113-C-T

Inheritance: autosomal recessive

Variant Evidence:

EXTL3, HGNC:3518

Neuro-immuno-skeletal Dysplasia Syndrome

OMIM: 617425

PMID: 30498080

Gene: ICOSLG

Disease: Combined Immunodeficiency

MonDO: MONDO:0015131

InheritancePattern: Autosomal recessive pattern

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

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

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

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: 2 different variants, unsure of cis or trans

CasePreviousTesting: n/a

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

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

ClinVar: n/a

CAID: CA406004676 , CA658820662

gnomAD: neither in gnomAD

GroupPresentingHPOs: HP:0008344 (elevated A keto acids in urine)

HPOsFreeText:

GroupNotHPOs:

NotHPOsFreeText:

NumberMales: 4

NumberFemales: 4

CountryOrigin: mainland China

Ethnicity:

Race: Chinese

AgeRange: 2 y 3 mo- 4 y 3 mo (present age)

TotalNumber: 8

VariantCount: 8 (subunits of BKDC: either BCKDHA, BCKDHB, or DBT)

NonVariant: 0

OtherVariant: 0

GroupPreviousTesting: n/a

GroupMethod1: PCR

GroupMethod2: Multiple sequence alignments

GroupGenotypingMethod: genomic DNA extracted from peripheral blood lymphocytes of patients and parents using TIANamp Blood DNA Kit. Exons and flanking intronic regions of BCKDHA, BCKDHB, and DBT were amplified with PCR and sequenced. Results compared with reference sequences in UCSC genome (BCKDHA (NM_000709), BCKDHB (NM_183050), DLD (NM_000108), DBT (NM_001918)), and compared with integrated set of variants from 1000 Genome Project to identify mutations. PolyPhen-2 and Mutationtaster program predicted the impact of missense alterations on protein function. Multiple sequence alignments obtained using BLAST.

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

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

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

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: unsure cis or trans

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

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

ClinVar: neither found

CAID: CA364659935, CA142287564

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

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

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

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

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: homozygous mutation

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

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

ClinVar: not found

CAID: CA969877

gnomAD: not found

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

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

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

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: variants also found in parents

Case (Level 2)

CasePreviousTesting: same as group

CaseMethod1: same as group

CaseMethod2: same as group

CaseGenotypingMethod: same as group

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

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

CAID:

gnomAD:

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

ClinVar: not found

CAID: CA406012849

gnomAD: not in gnomAD

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

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

CaseVI-4: Male, 3.5 years, Turkey

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

HPOsFreeText: -3.76 standard deviation score

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

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

CaseAddInfo: Variant is asserted de novo and confirmed by parental testing, Proband is hemizygous for this mutation

CasePreviousTesting: Calcium levels (9.8 mg/dL), Decreased serum phosphate levels (2.8 mg/dL; reference 3.8-6.5), Elevated serum ALP (925 IU/L; reference 90-325), 25OHD3 levels (35 ng/ml), 1,25(OH)2D3 levels (N/A pg/mL), PTH levels (62.2 ng/L), TPR levels (69.7), Decreased TmP/GFR levels (1.95; reference 2.9-6.1)

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

Variant: NM_000444.5:c.1217G>T (p.Cys406Phe)

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

gnomAD: Not in gnomAD

3 individuals with this variant, but they are previously reported. PMIDs: 20417570, 20157015

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

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

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

Shi, 2016 - A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification

PMID: 27943471

Gene: RAB39B

Disease: early-onset parkinsonism-intellectual disability syndrome

MonDO: MONDO:0010709

Case# P7, 2yo report

CasePresentingHPOs HP:0005528, HP:0001873

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

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

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

ClinVar 242372

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

Case# P5, 7yo report

CasePresentingHPOs HP:0005528, HP:0001873

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

CaseMethod1 NGS

CaseMethod2 Sanger

CaseGenotypingMethod NGS then variant confirmed with Sanger

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

ClinVar 446530

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

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

This paper uses in silico predictors to evaluate variants. Prediction is severe for this variant.

ExperimentName: Mutt mice have a FBXO11 S244L mutation

NonHumanModel: mouse (mus musculus)

GeneAlteration: ENU (ethylnitrosourea) was used to induce random mutatgeneiss in the mouse (PMID: 10932191). Animals were screened based on the development of otitis media. Sequencing of the mouse genome uncovered a single point mutation in the FBXO11 gene resulting in a Ser244Leu protein change. This mutation occurs in the region between the F-box and CASH domain. The Ser at amino acid position 244 is conserved across several species.

ModelPhenotype: HP:0000708

Also cleft palate and craniofacial abnormalities

HumanPhenotype: HP:0000708

ModelEvidence: The Mutt mutant mice have a point mutation in FBXO11, S244L. Heterozygous Mutt mice displayed reduced startle reflex at postnatal day 48. They also showed mild cranialfacila abnormalities including a shortened face. The Mutt homozygtote mice demonstrated perinatal lethality within the first day after birth in 17% of mice, but was much less severe than the Jeff mutant mice. the Jeff mice. Furthermore, that homozygotes mice had mild cleft palate and variable facial clefting, and the surviving homozygotes went on to develop craniofacial abnormalities including short face as well as reduced hearing.

ModelVariant: NM_001190274.1:c.983C>T (p. Ser328Leu) equivalent to ENST00000402508.5:c.731C>T (p. Ser244Leu)

CA ID: CA346766144

Case1: Male, 3 months onset, Australia

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

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

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

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmed

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

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

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

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

gnomAD: Not in gnomAD

Case2: Male, Birth onset, Australia

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

HPOsFreeText: Type 2B fibers absent

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

NotHPOsFreeText: N/A

CaseAddInfo: Variant is de novo with parental testing confirmation

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

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

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

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

gnomAD: Not in gnomAD

Family4: Australia

FamilyPresentingHPOs: HP:0002460, HP:0003701, HP:0000508, HP:0003803, HP:0003755 (Distal muscle weakness, Proximal muscle weakness, Ptosis, Type 1 muscle fiber predominance, Type 1 fibers relatively smaller than type 2 fibers)

HPOsFreeText: Type 2B fibers absent

FamilyNotHPOs: HP:0001249, HP:0030177, HP:0003798 (Intellectual disability, Abnormal nerve conduction study, Nemaline bodies)

NotHPOsFreeText: N/A

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

FamilyGenotypingMethod: Two methods were used for genotyping. In 16 patients, the 10 exons spliced onto the muscle-specific isoform of TPM3 were bidirectionally sequenced from genomic DNA. For the other 7 patients, complementary DNA was generated from patient muscle and isoform-specific primers were used to sequence the transcript. In this family, 14 further DNA samples were sequenced and a LOD score analysis was performed.

FamilyAddInfo: Affected members of this family seem to have different symptoms based on age

FamilyPMIDs: N/A

Affected: 5

Segregations: 6

PublishedLOD: 3.01 at θ = 0

AddSegregationInfo: Candidate Gene Sequencing

ProbandLabel: Case 5

Variant: NM_152263.4(TPM3):c.298C>A (p.Leu100Met)

ClinVar: 12452 https://www.ncbi.nlm.nih.gov/clinvar/variation/12452/

gnomAD: Not in gnomAD

Metodiev, 2016 (AJHG)

-2 cases with variants:

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

NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

-variant evidence

-rescue patient cells experiment

PatientCell CL:0000057 (fibroblast)

GeneFunction GO:0070131 (positive regulation of mitochondrial translation)

GeneAlteration n/a

FunctionalEvidence (Figure 2D) Labelling patient fibroblast proteins with EasyTag EXPRESS35S Protein Labeling Mix showed decreased assembly of complex I (NDUFB8) and IV (COXI) which corroborates the reduced mean enzyme activity and mitochondrial translation in Table 1.

FAVariants NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar: 224317

and

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

ClinVar: 224316

NM_017819.3(TRMT10C):c.814A>G (p.Thr272Ala)

ClinVar 224317

CAID CA10575895

gnamAD n/a

550+3A>C: Minigene analysis showed aberrant splicing in nearly 100% of mutated minigene construct transcripts, confirmed exon 3 splicing disruption

686-7C>G: RT-PCR and fragment analysis. Both patient sample results show 2 peaks (WT shows only 1)—reference transcript peak and a peak corresponding to a 6 bp longer transcript using a de novo created acceptor splice site. Aberrant and normal transcript proportion was roughly equal, which corresponds to complete impairment caused by the variant. The variant preserves a reading frame and leads to incorporation of additional two amino acids (proline-alanine) into the polypeptide chain

Variants: c.550+3A>C; c.686-7C>G

CAIDs: CA2573332696;

This variant is mentioned in reference to previously published papers that report IEMs

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

TissueExpression/Uberon ID: UBERON:0002113, UBERON:0000955, UBERON:0001987, UBERON:0002108, UBERON:0002048

ExpressionEvidence: Northern Blot analysis showed ubiquitous expression of COH1 transcripts in all tissues analyzed.

Relative quantification and PCR-based fragment analysis revealed expression of the splicing variant (NM_152564.3 utilizing exon 28b) in most human tissues. Almost equal expression of both full-length transcript (NM_017890.3 utilizing exon 28) and splice variant was found for fetal and adult brain as well as adult retina.

Where in paper: Results, under "COH1 is differentially spliced in human brain"

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

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

CaseMethod1 WES

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

ClinVar 446529

CaseAddInfo previously in 28202457

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

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

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

ClinVar 242372

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

CA3281947

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

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

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

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

CaseNotHPOs HP:0002540, HP:0001987

NotHPOcont: Non-ambulatory, Hyperammonemia

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

CaseMethod1 WES

CaseMethod2 Sanger

CaseGenotypingMethod WES and cSNP results confirmed with Sanger

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

ClinVar (1) 208823

CAID (1) CA358646

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

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

CaseAddInfo nonconsanguineous, parents confirmed heterozygotes

CasePMIDs n/a

PMID: 7666404

Variant NM_001368894.2:c.1225G>C(p.Gly409Arg)

Gene: PAX6

Disease: Ocular dysgenesis

InheritancePattern: AD

Notes SNP at last nucleotide in exon 13 leads to loss of donor site and exon skipping event.

PMID 19092807 Gene: UNC80

Case: Family D/Prendiville Patient 4, male, 12yo, American, Causasian

CasePresentingHPOs: HP:0100651, HP:0000953, HP:0000998, HP:0005912, HP:0001993

CasePresentingHPOsFreeText: Hyperpigmentation onset at 10yo; located on proximal anterior thighs initially, but spread to chest, lower back, abdomen, thighs, and posterior lower legs. Decreased IgM.

CaseNOTHPOs: HP:0002716, HP:0001433, HP:0003493, HP:0001999, HP:0004322, HP:0001738

CaseNOTHPOSFreeText: inflammatory symptoms

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

CaseGenotypingMethod: homozygosity mapping (50K SNP array), candidate gene sequencing

Variant: M116R homozygous

ClinVarID: or CAID: CA114353

gnomAD: This missense variant, p.M116R, is present in gnomAD v4.0.0 with a MAF=0.0001517 (179/1180030 alleles) in the European NF population and 0 homozygotes. Downscoring for homozygosity since parents are consanguineous.

AddCaseInfo: consanguineous parents

PreviouslyPublished: 17461801

VariantEvidence: Functional studies in Xenopus oocytes expressing M116R displayed a near-total loss of transport activity compared to WT SLC29A3. Studies in NIH 3T3 fibroblasts demonstrated mistrafficking of the mutant protein to the ER or Gogli apparatus (Kang et al. 2010; PMID: 20595384).

Case: Family A/Prendiville Patient 1, male, 14yo at report, East Indian

CasePresentingHPOs: HP:0004322, HP:0000343, HP:0030084, HP:0001993, HP:5000011, HP:0003261, HP:0000953, HP:0000998, HP:0000520, HP:0001433, HP:0012094, HP:0430023, HP:0003565, HP:0001935, HP:0012343, HP:0040303, HP:0100651, HP:0004322, HP:0001999, HP:0100534, HP:0000670, HP:0000767, HP:0031664, HP:0002716, HP:0001763, HP:0001698

CasePresentingHPOsFreeText: hyperpigmentation onset at 15yo; located on chin, axillae, back, abdomen. inner thigh, inguinal folds, genitalia. Pancreatomegaly. Orbital thickening and EOM infiltrate on MR/CT. Opacification of the maxillary sinuses. Posterior pericardial thickening. Thickened right atrial wall.

CaseNOTHPOs: HP:0001738

CaseNOTHPOSFreeText: inflammatory symptoms

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

CaseGenotypingMethod: homozygosity mapping (50K SNP array), candidate gene sequencing

Variant: E444X homozygous

ClinVarID: or CAID: CA114350

gnomAD: This nonsense variant p.E444X, located in exon 6/6, is present in gnomAD v4.0.0 with a MAF=0.0002525 (23/91078 alleles) in the South Asian population and 1 homozygote. Downscoring this variant since NMD is not expected to occur and there is 1 homozygote in gnomAD.

AddCaseInfo: consanguinity not reported

PreviouslyPublished: 17461801

VariantEvidence: Functional studies in Xenopus oocytes expressing E444X displayed a partial reduction in nucleoside transport activity and impaired protein stability.

PMID: 35782621

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case# B1-4, Male, UK

CasePresentingHPOs HP:0001279

CasePreviousTesting re-sequenicing of genome

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

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

ClinVar 36873

gnomAD 0.03553 link

Case# A2, Male, UK

CasePresentingHPOs HP:0002119

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# B4, Male, UK

CasePreviousTesting re-sequenicing of genome

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

Variant NM_024334.2(TMEM43):c.424G>A (p.Glu142Lys)

ClinVar 46147

gnomAD 0.001121 link

Case# Subject 10, female, 14yo, non-Hispanic

CasePresentingHPOs HP:0010535, HP:0002098, HP:0031064, HP:0000729, HP:0000750, HP:0001249, (Sleep apnea, Difficulty breathing, Impaired continence, Autism spectrum disorder, Speech delay, Intellectual disability)

HPOFreeText: Phenotypes described postnatally.

CaseNotHPOs HP:0001250, HP:0001252, HP:0000708, 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:0002938, HP:0001511, HP:0011328, HP:0002007, HP:0000325, HP:0000534, HP:0000601, HP:0000316, HP:0000582, HP:0000494, 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:0010490, HP:0000349, HP:0004532, HP:0000957 (Seizures, Hypotonia, Behavioral problems, Spastic quadriparesis, ADHD, Poor feeding, 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, Gastroesophageal reflux, Duodenal atresia, Annular pancreas, Pyloric stenosis, Vesicoureteral reflux, Cystic kidney, Syndactyly, Hip dysplasia, Scoliosis, Lumbar lordosis, Intrauterine growth retardation, Fontanel abnormality, Frontal bossing, Triangular face, Abnormal eyebrows, Hypotelorism, Hypertelorism, Upslanting palpebral fissures, Down-slanting 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, Abnormal palmar creases, Widow's peak, Sacral hypertrichosis, Café Au Lait spots)

CasePreviousTesting Screen for variants involved with Autism, de novo RERE variant was only result

CaseMethod1 Exome sequencing

CaseMethod2 sanger

CaseGenotypingMethod exome sequencing confirmed with sanger in patient and parents by Krumm et al.

Variant NM_012102.3:c.2278C>T(p.Gln760Ter), de novo

ClinVar n/a

CAID CA338172916

gnomAD n/a

VariantEvidence n/a

CaseAddInfo both parents tested

CasePMIDs 25961944

Case#: (Biallelic affected sib) MM, female, 10 years (at age of blood draw) CaseHPOs: HP:0002024, HP:0002013, HP:0002570, HP:0002495, HP:0001284 (malabsorption, vomiting, steatorrhea, , impaired vibratory sensation, absent deep tendon reflexes)

CaseHPOsFreeText:: Diagnosed with FHBL at age 10 years; neurological symptoms stabilized on Vitamin E treatment. CasePreviousTesting: Total cholesterol 24mg/dl, no detectable triglyceride ot LDL-cholesterol, 21 mg/dl HDL cholesterol. Variant: Compound heterozygous: Variant 1: NM_000384.2:c.537+1G>T (paternal) Variant 2: NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

ClinVar: N/A

CAID: Variant 1: CA345962364 ; Variant 2: CA052017

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

Case#: (Heterozygous sib) GM (II-5), male, 14 years (at blood draw), sib of proband CaseHPOs: HP:0003563 CaseHPOsFreeText: Asymptomatic CasePreviousTesting: Total cholesterol 97 mg/dl, triglyceride 59 mg/dl, LDL-cholesterol 29 mg/dl (<5th percentile), HDL cholesterol 56 mg/dl. ** Variant:** Heterozygous for NM_000384.2:c.537+1G>T (paternal)

CAID: CA345962364

Case#: (Heterozygous sib) JM (II-6), male, 7 years (at blood draw), sib of proband CaseHPOs: HP:0003563 CaseHPOsFreeText: Asymptomatic CasePreviousTesting: Total cholesterol 113 mg/dl, triglyceride 60 mg/dl, LDL-cholesterol 16 mg/dl (<5th percentile), HDL cholesterol 87 mg/dl) ** Variant:** Heterozygous for NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

CAID: CA052017

Case#: Speigel Patient I-1, onset at birth, death at 10mo

DiseaseAssertion: Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy

FamilyInfo: Parents are healthy first-degree cousins with no visual or neurological complaints. Both parents were heterozygous for this OPA1 variant. Their optic discs did not look pale on dilated fundus examination and optical coherence tomography (OCT) imaging did not show any subclinical thinning of the retinal nerve fibre layer. The parents have two clinically unaffected sons who were 14 and 11 years old when last reviewed in clinic. The older son is heterozygous for the c.1601T>G OPA1 variant, whereas the other son only carries the wild-type OPA1 allele.

CasePresentingHPOs: HP:0001622, HP:0001531, HP:0008936, HP:0001276, HP:0002179, HP:0001612, HP:0000617, HP:0031964, HP:0012758, HP:0001639, HP:0002104

CaseHPOFreeText: elevated lactate levels, but a normal cerebrospinal fluid (CSF) lactate concentration. progressive, non-obstructive, generalised hypertrophic cardiomyopathy,

CaseNotHPOs: HP:0001635

CaseNotHPOFreeText: abnormal brain MRI

GenotypingMethod: genome-wide autozygosity mapping and next-generation exome sequencing

PreviouslyPublished: n/a

Variant: OPA1 NM_015560.2 c.1601T>G p.Leu534Arg

ClinVar:

CAID: CA357235

SupplementalData: n/a

PMID: 1522213

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

ExperimentName: Expression of variant carrying cDNA in GALNS deficient fibroblasts

FunctionalEvidence: cDNA encoding each of the 15 variants identified in the study were transfected into a GALNS deficient fibroblast cell line. 14 of the 15 altered cDNA's showed no increase in GALNS activity when the cells were assayed, confirming a lack of enzymatic activity.

HGNC:

GeneEvidence:

SharedGeneImplication:

Case#: Wilson_Australian kindred_Person II:2

Demographics: Male, 44y at diagnosis, Australia

CasePresentingHPOs: HP:0000750, HP:0001249, HP:0007351, HP:0002362, HP:0002067, HP:0100660, HP:0002396, HP:0000256

Age at onset <2y, while age at tremor onset was 38y. Birth and early milestones were normal. Early learning difficulties were reported and the proband was able to read and write. Parkinsonism classification was akinetic-rigid. Proband showed L-Dopa response, hypokinetic dysarthria, and normal cerebellar function. Other normal features included normal eye examination, MRI, Fragile X testing, karyotype, Copper testing, blood count and chemistry, urine metabolic testing and hearing.

CaseNotHPOs:

CasePreviousTesting: Linkage analysis using homozygous recessive model identified no linkage to autosomes, but to two regions: Xp22.2 and Xq27.3–qter

CaseMethod1: Copy number variation analysis

CaseMethod2: PCR