PMID: : 42824042

Gene: MYBPC3

HGNC ID: :7551

PMID: 42698999

Gene: TNN

HGNC ID:11949

PMID: 41726140

Gene: MYBPC3

HGNC ID: 7551

Whole genome sequencing in paediatric channelopathy and cardiomyopathy

PMID: 38586174 Gene: MYBPC3 HGNC ID: 7551

Case2: 12-year-old boy (Patient 2) DiseaseAssertion: DCM FamilyInfo: Family history unremarkable. ParentalTesting: The MYBPC3 variant was inherited from his father. The father’s cardiac phenotype is not reported. CasePresentingHPOs: HP:0001644, HP:0003546 CaseHPOFreeText: Severely depressed biventricular function; heart transplantation for decompensated heart failure. CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Previous WES was negative; the variant’s intronic region was not adequately covered. Genotyping Method: Whole-genome sequencing (WGS; Illumina NovaSeq 6000; aligned to hg19/GRCh37). FunctionalAnalysis: SpliceAI predicted a potential splicing effect; no functional assay in this patient is reported. Variant: NM_000256.3:c.1224-80G>A (heterozygous intronic variant) ClinVar: 693982 CAID: CA221697326 gnomAD: 0.0000637 AdditionalInfo: The authors classified the variant as a VUS in this DCM case because evidence for a MYBPC3–DCM relationship is limited. ClinVar currently reports a pathogenic/likely pathogenic aggregate classification, primarily in relation to HCM. Reanalysis found no second MYBPC3 variant.

Case#: Family 1, individual II-5

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: The proband has a family history of DCM. His father and brother also had DCM and died from heart failure at ages 69 and 63 respectively. The disease follows an autosomal dominant inheritance pattern.

ParentalTesting: Want reported, his father had DMC but this article does not confirm genetic testing of his parents.

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644) & left ventricular systolic dysfunction (HP:0005162)

CaseHPOFreeText: The proband was diagnosed with DCM at age 45 and received medication for heart failure. At the time of the study he was 66 years old. His echocardiogram showed an enlarged left ventricle and reduced heart function with an ejection fraction of 33%.

CaseNotHPOs: NR

CaseNotHPOFreeText: The researchers reported no other structural heart diseases or conditions contributing to DCM in the affected family members, including coronary heart disease, valvular heart disease, viral myocarditis and hypertension.

CasePreviousTesting: ECG, clinical examination and routine laboratory testing were part of the study assessment. The probands echocardiogram showed a left ventricular end diastolic diameter of 63 mm and an ejection fraction of 33%.

Genotyping Method: Genome wide microsatellite screening, genetic linkage analysis, whole exome sequencing and sanger sequencing.

FunctionalAnalysis: Laboratory experiments showed that the KLF13 E144X mutation reduced the proteins ability to activate the heart related genes ACTC1 and MYH7. The mutation also affected DNA binding cooperation with GATA4 and normal nuclear localization.

Variant: KLF13 c.430G >T

Clinvar: NR

CAID: CA391891162

gnomAD: The researchers reported that the variant was absent from gnomAD and other population databases at the time of their study. No numerical allele frequency was provided.

AdditionalInfo: The proband is a male from a 4th generation Chinese family. His KLF13 mutation was associated with familial DCM. the researchers found that the mutation was shared by affected family members and was absent from unaffected family members and 418 unrelated healthy controls.

Case#: Family 2, III-10 47 year old female

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Multiple family members had DCM. The disease followed an autosomal dominant inheritance pattern.

ParentalTesting: NR

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)

CaseHPOFreeText:Female aged 47 with DCM. Her left ventricular end diastolic diameter was 57mm and her ejection fraction was 40%.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Echocardiogram and clinical cardiac evaluation.

Genotyping Method: Sanger sequencing of KLF13

FunctionalAnalysis: The E194X mutation reduced the ability of KLF13 to activate ACTC1 and MYH7 and bind their promoters. It also disrupted cooperation with GATA4.

Variant: KLF13 c.580G>T

Clinvar: NR

CAID: NR

gnomAD: The variant was reported as absent from gnomAD at the time of the study.

AdditionalInfo: The mutation was found in affected family members and was absent from 418 unrelated healthy controls.

Case#: Family 3, III-4

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: The family had multiple cases of DCM consistent with autosomal dominant inheritance.

ParentalTesting: NR

CasePresentingHPOs: Dilated cardiomyopathy (HP:0001644)

CaseHPOFreeText: Female age 41 with DCM. her left ventricular end diastolic diameter was 58 mm and her ejection fraction was 43%.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: Echocardiogram and clinical cardiac evaluation

Genotyping Method: Sanger sequencing of KLF13

FunctionalAnalysis: The C199R mutation reduced KLF13 ability to activate ATC1 and MYH7 bind DNA and work together with GATA4.

Variant: KLF13 c.595T>C

Clinvar: NR

CAID: CA391512228

gnomAD: The variant was reported as absent from gnomAD at the time of the study.

AdditionalInfo: The variant was associated with familial aDCM and was not detected in the 418 healthy controls.

Novel Intragenic PAX6 Deletion in a Pedigree with Aniridia, Morbid Obesity, and Diabetes

PMID: 31361967

Gene: MYBPC3

HGNC ID: 7551

Case1: 50 year old male DiseaseAssertion: HCM; hydroxychloroquine cardiotoxicity FamilyInfo: Six children undergoing predictive testing for the familial MYBPC3 variant; family history not reported ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: Monomorphic ventricular tachycardia, dyspnea, nausea, vomiting, biventricular hypertrophy, systolic dysfunction, cardiogenic shock CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Prior CMR showed nonobstructive HCM; cardiomyopathy gene panel identified the variant Genotyping Method: Cardiomyopathy gene panel FunctionalAnalysis: Altered splicing with exon 30 skipping; authors describe a nonfunctional protein or premature stop codon Variant: c.3330+5G>C ClinVar: 42706 CAID: gnomAD: 0.03% (as reported in the article) AdditionalInfo: Long-term hydroxychloroquine exposure for malaria prophylaxis; biopsy findings were consistent with both HCM and hydroxychloroquine cardiotoxicity

Chronic Activation of Tubulin Tyrosination Improves Heart Function

PMID: 39279670 Gene: MYBPC3 HGNC ID: 7551

PMID: 34588271

Gene: MYBPC3

HGNC ID: HGNC:7551

33101033

MyBPC3

HGNCID:7551

Table 1 identifies individual Slovenian probands carrying MYBPC3:c.913_914del and compares genetic markers used for haplotype analysis

Table 3 compares heart measurements between probands with MYBPC3:c.913_914del and those with other MYBPC3 variants. These measurements help evaluate how the variants relate to heart structure and function

Table 2 compares clinical symptoms and characteristics between 18 probands with MYBPC3:c.913_914del and 21 probands with other likely pathogenic or pathogenic MYBPC3 variants. The differences shown were not statistically significant.

Quote from Introduction:

I remember when it was all done in first draft telling Gene Wolfe, who is the wisest writer I know and has written more excellent novels than any man I’ve met, that I thought I had now learned how to write a novel. Gene looked at me, and smiled kindly. “You never learn how to write a novel,” he told me. “You only learn to write the novel you’re on.”

Gaiman, Neil. 2021. American Gods: A Novel. 10th Anniversary. New York: William Morrow Paperbacks.

Case#: Meireles_Proband_2 (assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: None

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity

CaseNotHPOs: N/A

CasePreviousTesting: None

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Trp)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

PMID:22754241

Gene:F8

HGNC ID:3546

PMID: 26063760

Gene: F9

HGNC: 3551

Case#: Gostout_Proband_280 (assumed male, Asian (from Japan))

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: None

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (FIX:C: 1.8%)

CaseNotHPOs: None

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 28491642

Gene: ACTC1

HGNC ID: 143

A novel ACTC1 mutation in a young boy with left ventricular noncompaction and arrhythmias PMID: 28491642

Gene: ACTC1

HGNC ID: 143

PMID: 31510962

Gene:GAA

PMID: 31076647

Gene GAA

Case#: 84, Gender N/A, 6 months old when diagnosed, Asian

DiseaseAssertion: Pompe disease

FamilyInfo: Both parents were tested for variants in GAA

CasePresentingHPOs: N/A

CaseHPOFreeText:N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: The patient did not present any symptoms, diagnosed was made based on the predicted impact of the variant by PolyPhen-2

CasePreviousTesting: The GAA gene was sequenced using NGS and resequenced for confirmation using Sanger.

Dried Blood spot test found an GAA activity of 3.8 pmol/h/disk with a reference value of 6.5 pmol/h/disk

enzyme activity in fibroblast was recorded to be 3.0 nmol/h/mg protein.

Variants: Variant1: (Two mutated alleles with heterozygous mutations)

Variant1.1: NM_000152.5(GAA):c.752C>T (p.Ser251Leu)

ClinVar: 346310

CAID: CA8815007

gnomAD: Highest population MAF = 0.002234 (East Asian)

Variant1.2: NM_000152.5(GAA):c.761C>T (p.Ser254Leu)

ClinVar: 330447

CAID: CA8815009

gnomAD: Highest popu;ation MAF= 0.002235 (East Asians)

Variant2: C.1244C>T

ClinVar: N/A

CAID: N/A

gnomAD: N/A

ParentalGenotype: The c.752C>T+c.761C>T and c.1244C>T of subject ID 84 were derived from mother and father, respectively

PreviouslyPublished:N/A

PMID: 30371346

Gene: GAA

PMID: 32102177

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO:

InheritancePattern: AR

PMID: 38606545

Gene: TERC

Disease:

MonDO:

InheritancePattern:

Notes:

Implicating short telomeres (TBD) is the underlying mechanism of disease

Linking DKC with Pulmonary disease

PMID 17392301

PMID: 25252036

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

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:

Case#: He_12

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

CaseGenotypingMethod: Sanger of GALNS exons

Variant: p.R386C & p.W403_T404delinsCS

ClinVar: 700 & 1048331

CAID: CA221040 & CA916079760

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

Case#: He_21

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

CaseGenotypingMethod: Sanger of PCR amplified GALNS exons 1-14

Variant: p.W520X & p.G290R

ClinVar: 1048427 & 93171

CAID: CA397076034 & CA221049

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

PMID: 24035930

Gene: GALNS

Disease: Mucopolysaccharidosis type IVA

MonDO: MONDO:0009659

InheritancePattern: AR

GroupPresentingHPOs: only shared phenotype was reduced GALNS activity in leukocytes

GroupGenotypingMethod: Sanger seq of amplified exons

NumberMales: 15

NumberFemales: 6

NumberFamilies: 19

CountryOrigin: China

AgeRange: 1yo to 7.8yo

TotalNumber: 21

FamilyInfo:19 families, siblings P1 and P2, P3 and P4, parents were studied for segregation info

VariantCount: 15

PMID 21436073

Diesease Bone marrow failure linked to pulmonary fibrosis

PMID: 14583446

Gene: GALNS

Disease: mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

NonHumanModel: Murine

GeneAlteration: murine Galns portions of intron 1 and exon 2 were deleted via homologous recombination of a cre-neomycin resistance-cre cassette and mated with a cre recombinase strain to remove the cassette and complete the deletion

ModelPhenotype: No outward phenotypes but biochemically there was up to a 6 fold increase in GAG excretion in urine, chondroitin-6-sulfate specifically and not keratan sulfate, consistent with the human phenotype

HumanPhenotype: in severe cases there are obvious skeletal deformations, increase of GAG's chondroitin-6-sulfate and keratan sulfate in urine and decreased or absent GALNS activity

ModelEvidence: X-rays of mice and multiple life stages, GAG assays in urine, immunohistochemistry images of tissues with labeled chondoritin-6-sulfate and keratan sulfate to show distribution in multiple tissue types and

ModelVariant: large deletion of portion of intron 1 and exon 2

WhereInPaper:

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

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)

PMID 36151328

Gene TERC

Diseases dyskeratosis congenita, pulmonary fibrosis, Høyeraal–Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome

potential gene therapy targets to increase TERC (hTR)

Important Table of 16 known telomere biology disorder linked genes with synopses of associated diseases and case counts

Case#: Patient E (assumed male)

DiseaseAssertion: Severe, Familial Hemophilia B

FamilyInfo: Mothers were heterozygous, but patient E’s sister and aunt were non-carriers (homozygous for the cleavage)

ParentalTesting: Mothers were heterozygous, but patient E’s sister and aunt were non-carriers (homozygous for the cleavage)

CasePresentingHPOs: HP:0011858

CasePresentingHPOsFreeText: reduced factor IX activity (FIX:C: <1; FIX:Ag:37/38)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.135G>T (p.Lys45Asn)

ClinVar: Absent/Not Reported

CAID: CA414435576

gnomAD: Absent/Not Reported

PMID: 8213840

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: V:3

Demographics: Pakistani

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

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: Proband whole exome seq

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

ClinVar: 1048200

CAID: CA8235027

gnomAD: 16-88902194-C-T

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

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

CasePMIDs:

PMID: 36292628

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes: Case report

PMID 22830481

Disease Pulmonary fibrosis/ bone marrow failure syndrome

PMID: 8829629

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

NonHumanModel: Mus musculus

GeneAlteration: p.Arg386Cys the most frequently reported missense variant linked as a causal pathogenic allele in mucopolysaccharidosis IVA patients

ModelPhenotype: In addition to undetectable GALNS enzyme activity in any assayed tissue, increased keratan sulfate detection in liver tissue and blood serum, the boney deformations missing from previous models were present in this mouse model HP:0004325, MP:0001258, HP:0005736

HumanPhenotype: HP:4000197, HP:0012069, HP:0004322, HP:0005736

ModelEvidence: CRISPR/Cas9 directed site mutagenesis of murine Galns coding sequence at codon homologous to the human p.Arg388Cys mutation cited in human MPSIVA patients. Mouse model showed increased keratan sulfate accumulation in liver and blood serum, undetectable n-acetylgalactosamine-6-sulfatase activity in any body tissue assayed as well as skeletal deformities consistent with human MPSIVA patients

ModelVariant: p.Arg388Cys

WhereInPaper:

PMID: 34504088

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

RescueModel: Rescue WT CAG::GALNS in murine model by ovexpression in a Galns variant frequently found in human's affected with MPSIVA

GeneAlteration: transduction by AAV9 of CAG promoted WT murine optimized Galns coding sequence. Widespread tissue transduction was visualized with a CAG promoted GFP cassette delivered by AAV9, subsequently GFP production was widespread and found in all relevant tissue including osteoblast rich areas.

RescueVariant: AAV9-Galns with the coding sequence under the control of a CAG promoter element

RescuePhenotype: HP:0004325, MP:0001258, HP:0005736

RescueMethod: p.Arg386Cys (MPSIVA) mice were first transducted with CAG::GFP via AAV9 to verify efficiency of delivering the coding sequence to target tissue like bone. Then a CAG::Galns (optimized WT) was transducted in to MPSIVA mice (Galns -/-) via AAV9 by 4 weeks of age to avoid the high mortality in the Galns homozygote starting at 2 months.

RescueEvidence: Early transduction of Galns -/- mice recovered higher than WT enzyme activity and WT levels of keratan sulfate detected in liver tissue. Abnormalities in the growth plate in Galns -/- mice were absent in those treated with AAV9-Galns resulting from a return to WT levels of enzyme activity and keratan sulfate in all bone tissue sampled. GALNS activity recovered in lung and heart tissue with the elevated heart rate in MPSIVA mice returned to WT.

ModelVariant: p.Arg386Cys

Family#PresentingHPOs: P1: HP:0000943, HP:0008922, HP:0002650, HP:0001537, HP:0020152, HP:0002515, HP:0002808, HP:0007957, HP:0008480, HP:0005180, HP:0002857,HP:0012069, HP:0002870 P2:HP:0001537, HP:0002857, HP:0007957, HP:0005180, HP:6000342, HP:0001385, HP:0000768, HP:0100559, HP:0012069 occipitocervical stenosis, myelomalacia

FamilyNotHPOs:

CountryOrigin:

Ethnicity:

Race:

Family#PreviousTesting:

Family#Method1:

Family#Method2:

Family#GenotypingMethod: unspecified NGS technique followed by GALNS specific Sanger seq of exons and targeted intronic regions

Affected: 2

Unaffected: 2

Segregations:

PublishedLOD:

eLOD:

AddSegregationInfo:

ProbandLabel: DeLong_P1, DeLong_P2

Variant: NM_000512.5(GALNS):c.899-397_1003-1862del

ClinVar: 1048483

CAID: CA2499223751

gnomAD: n/a

FamilyAddInfo:

FamilyPMIDs:

PMID: 36245961

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/ Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

PMID: 27825773

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Notes:

Case#: Fateen_P4

Demographics: Egyptian

CasePresentingHPOs: HP:0000768, HP:0000943, HP:0002857, HP:0000256, HP:0002808, HP:0001382, HP:0005072, HP:0009769 prominent proximal metaphyses

CaseNotHPOs:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: single gene seq by Sanger of all 14 exons and restriction digest confirmation/ screening of parents and controls

Variant: NM_000512.5(GALNS):c.119A>G (p.Asp40Gly)

ClinVar: 1048369

CAID: CA397100962

gnomAD: n/a

VariantEvidence: hydrophillic>hydrophobic substitution in putative active site and enzyme activity data shows low enzyme function compared to reference range

CaseAddInfo:

CasePMIDs:

PMID 22079513

Disease Idiopathic pulmonary fibrosis

Animal Models telomerase deficiency was studied in mouse models prior to their discovery in association with human disease, with dyskeratosis congenita being the first to be associated with TBD

Case#: HB-KHF-04 (Male, Korean)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Among the 33 patients, 13 had a family history (39%), while the rest of the patients did not (sporadic, 61%). 27 patients (82%) had the severe form of the disease, while 6 patients (18%) had the moderate form

ParentalTesting: N/A

CasePresentingHPOs: HP:0003645, HP:0011858

CaseHPOsFreeText: Prolonged partial thromboplastin time, reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: aPTT and one-stage clotting assay at labs where patients were ascertained: FIX-deficient plasma (STA®-Deficient IX; Diagnostica Stago, Asnieres-sur-Seine, France; reference range, 60–150%) at Samsung Medical Center or HemosIL™ (Instrumentation Laboratory, Milan, Italy; reference range, 50–145%) at the Korea Hemophilia Foundation.

Gene: F9

Variant: NM_000133.4:c.71T>C (p.Leu24Pro)

ClinVar: Absent

CAID: CA414434410

gnomAD: Absent/Not Reported

Case#: HB-KHF-25 (Male, Korean)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Among the 33 patients, 13 had a family history (39%), while the rest of the patients did not (sporadic, 61%). 27 patients (82%) had the severe form of the disease, while 6 patients (18%) had the moderate form

ParentalTesting: N/A

CasePresentingHPOs: HP:0003645, HP:0011858

CaseHPOsFreeText: Prolonged partial thromboplastin time, reduced factor IX activity

CaseNotHPOs: None

CasePreviousTesting: aPTT and one-stage clotting assay at labs where patients were ascertained: FIX-deficient plasma (STA®-Deficient IX; Diagnostica Stago, Asnieres-sur-Seine, France; reference range, 60–150%) at Samsung Medical Center or HemosIL™ (Instrumentation Laboratory, Milan, Italy; reference range, 50–145%) at the Korea Hemophilia Foundation.

Gene: F9

Variant: NM_000133.4:c.128G>T (p.Arg43Leu)

ClinVar: 993549

CAID: CA414435545

gnomAD: Absent/Not Reported

Case#: Chan_Hong Kong 2 & Chan_Hong Kong 3 (Southern Chinese, assumed male)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: Carrier testing of at risk females in each family was completed by direct restriction enzyme analysis after determination of the specific FIX defect for the index patient

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: reduced factor IX activity (Chan_Hong Kong 2 FIX:Ag: 0.93; FIX:C: 0.04) (Chan_Hong Kong 3 FIXAg: 0.82; FIX:C: 0.01)

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.128G>A (p.Arg43Gln)

LegacyVariant: c.6365 G>A (p.Arg-4Gln)

ClinVar: 810864

CAID: CA414435539

gnomAD: Absent/Not Reported

Case: VWD cohort index patients (IPs)

DiseaseAssertion: congenital bleeding disorder

FamilyInfo: Six index patients (IPs), from VWD cohort of patients of Germany and Pakistan

ParentalGenotype(s):

CasePresentingHPOs: HP:0000006

CaseHPOFreeText: IP1 (VWF:Ag (IU/dl)=12), IP2 (WF:Ag (IU/dl)=1), IP3 (VWF:Ag (IU/dl)=29), IP4 (VWF:Ag (IU/dl)= 1), IP5 (VWF:Ag (IU/dl)=35), IP6 (VWF:Ag (IU/dl)= 1)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Not provided

PreviouslyPublished:

Gene: VWF

Variant: IP1 c.164G>A (p.Gly55Glu), IP2 c.4019T>G, c.257T>A (p.Leu1340Arg , p.Val86Glu), IP3 c.571T>C (p.Trp191Arg), IP4 c.3797C>T, c.631A>G (p.Pro1266Leu, p.Asn211Asp) , IP5 c.3931C>T, c.1001G>A (p.Gln1311X,p.Gly334Glu) , IP6 c.2561G>A, c.1824C>G (p.Arg854Gln , p.Cys608Trp)

HGVS: NM_000552.4 and NP_000543.2

ClinVarID:https://www.ncbi.nlm.nih.gov/clinvar/?term=VWF%5Bgene%5D&redir=gene

CAID: 00311186–00311190

gnomAD:n/a

PMID: 30770309 Gene: GAA

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

PMID: 9660054

Gene: GALNS

Disease: Mucopolysaccharidosis IVA/Morquio A

MonDO: MONDO:0009659

InheritancePattern: AR

Family#PresentingHPOs: HP:0000884, HP:0005619, HP:0002761, HP:0012069

CountryOrigin: Poland

Family#Method1: SSCP

Family#Method2: Sanger

Family#GenotypingMethod: SSCP followed by sanger sequencing of mobility variants

Affected: 3

Unaffected: 2

Segregations: 3

eLOD: 1.45

AddSegregationInfo: II:2 and II:7 were not genotyped and not counted, III:1 and III:2 had a greater than 0.25 chance since mother was homozygous so they can not be counted

ProbandLabel: TM

Variant: R259Q and R94G

ClinVar: 706 & 705

CAID: CA251569 & CA251568

gnomAD: 16-88901743-C-T & n/a

PMID: 12721840

Gene: GALNS

Disease: Mucopolysaccharidosis IVA

MonDO: MONDO:0009659

InheritancePattern: AR

PMID: 12090986

Gene: TERC

Disease: Dyskeratosis congenita & bone marrow failure/pulmonary fibrosis

MonDO: MONDO:0007485, MONDO:0013879

InheritancePattern: AD

Notes: variants: NR_001566.1:n.58G>A, NR_001566.1:n.72C>G, NR_001566.1:n.110_113del

Case: 24-year-old Caucasian woman with a rare variety of type 2M VWD

DiseaseAssertion: 2M VWD

FamilyInfo: family history was negative for easy bruisability, bleeding, or clotting disorder but maternal grandmother had lung cancer.

CaseNOTHPOFreeText: Von Willebrand factor antigen 45% on 9/12/17 and 37% on 9/19/17 with the ratio of VWF activity to the antigen is less than 0.7

ParentalGenotype(s):Unknown

CasePresentingHPOs: HP:0003010 (Prolonged bleeding time), HP:0000978 (Bruising susceptibility).

**CaseHPOFreeText: ** loss of weight over the last six months, The complete blood count, comprehensive metabolic panel, factor VIII, prothrombin time and partial thromboplastin time, D-Dimer, and antithrombin activity were normal. Her von Willebrand factor activity was much lower compared to the antigen.

CasePreviousTesting: None

GenotypingMethod: Patient have not been genotyped

PreviouslyPublished: N/A

Variant: N/A

ClinVarID: N/A

gnomAD: N/A

**Gene: ** VWF Inheritance mode autosomal dominant variety with normal, high molecular weight multimers

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:

PMID 33407246

Disease Mucopolysaccharidosis IVA

Gene GALNS

PMID 18753630

Disease pulmonary fibrosis

ExperimentName: Accumulation of glycosaminoglycans

GOterm:

FunctionalEvidence: Patient cells assayed with artificial substrates for the N-acetylgalactosamine-6-sulfate sulfatase encoded by GALNS, depending on the severity of the coding sequence alteration, are either unable to break down the substrate or are hindered. Further, in mucopolysaccharidosis IVA patients with known variants, elevated levels of keratan sulfate and chondroitin-6-sulfate can be found in their urine where levels in unaffected individuals are much lower.

HGNC:

GeneEvidence:

SharedGeneImplication:

Case#: Male, Family #2, patient #4, onset at 48y.o

DiseaseAssertion: STGD

FamilyInfo: proband sister(#3) identical ABCA4 allele to proband, developed central vision issues. Proband son has complex allele w/ early onset cone-rod dystrophy. Proband daughter(#6) has complex allele mutation, central vision issues developed at 17. retinal exam showed atrophic macular lesions. Proband second daughter(patient #5, asymptomatic)

CasePresentingHPOs: HP:0012508, HP:0030500

CaseHPOFreeText:Proband presented with bull's eye macular lesions with no fundus flecks. Normal rod-mediated amplitudes, normal single-flash response, reduces 32-Hz flicker amplitude.

CaseNotHPOs: n/a

CaseNotHPOFreeText: maintained foveal sparing in both eyes 20/25+2 R.E, 20/25+1 L.E.

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: c.4139C>T (p.P1380L), BoldM1: c.5603A>T(p.N18681)[NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile) - Variation ID 99390], M2: c.[1622T>C; 3113C>T] (p.[L541P; A1308V])

ClinVar: M1) 99390 M2) 99067

CAID: n/a

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Female, Family #4, patient #8

DiseaseAssertion: STGD

FamilyInfo: Proband's daughter shares ABCA4 variant and struggled with difficulty focusing at age 19. BVCA 20/200 R.E and 20/80 in L.E.

CasePresentingHPOs: HP:0030500, HP:0007663, HP:0000608

CaseHPOFreeText: Proband's first symptom was difficulty with night vision occurring at 45 y.o, BVCA at 50 y.o in both eyes was 20/20. atrophy in macula and Stage 2 fundus flecks identified.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro), NM_000350.3(ABCA4):c.1957C>T (p.Arg653Cys)

ClinVar: M2) 99067, M5) 99108

CAID: n/a

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Male, Family#3, Proband M1, M2: II,1 on pedigree

DiseaseAssertion: STGD

FamilyInfo: mother of proband has p.N18681 and p.P1380L mutations and is asymptomatic with no changes to NIR-AF and SD-OCT. Treated with 400mg of hydroxychloroquine for lupus prior to imaging. Non-affected father.

CasePresentingHPOs:HP:0007663, HP:0000493

CaseHPOFreeText: Proband has reduced visual acuity and issues reading with BCVA 20/200 in R.E and 20/50-2 in L.E. Oval foveal lesions with stage 2 flecks. Visual acuity reducing starting at age 10.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: M1:p.P1380L, complex allele: M2: p.N18681 and IVS38:c.5461-10T>C. M3: c.4139C>T(p.P1380L)

ClinVar: M1) 99390 M2) 99067 M3) Variation ID: 7904

CAID: n/a

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Female, family #5, Patient #20

DiseaseAssertion: STGD

FamilyInfo: Proband's sister presented with same clinical prognosis. Sister diagnosed with pattern dystrophy and photoaversion at age 57, with difficulty seeing at night. Sister has nuclear sclerotic and cortical cataracts in both eyes.

CasePresentingHPOs: HP:0000662, HP:0000603, HP:0000603, HP:0000493

CaseHPOFreeText: Proband presented with localized blur at age 62, (late onset) in her left eye. BVCA 20/20-3 and 20/20-2 at age 70. Also has macular lesions with stage 2 fundus flecks.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: p.N18681, IVS36:c.5196+1G>A

ClinVar: M2) 99067, M6) 99351

CAID: N/A

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

PMID: 33633436 Gene:ABCA4 HGNC:34

Case#: Patient 231, Female, age of onset at 7 y.o, Poland

DiseaseAssertion: STGD1

FamilyInfo: Mother was a carrier, unaffected father.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.4234C>T , p.(Gln1412*)

ClinVar: 99263

gnomeAD 0.00001984 allelic frequency

CAID: n/a

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.634C>T,p.(Arg212Cys)

ClinVar: 7898

CAID: n/a

gnomeAD 0.0001177 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: Patient 231, Female, age of onset at 7 y.o, Poland

DiseaseAssertion: STGD1

FamilyInfo: Mother was a carrier, unaffected father.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.5882G>A

ClinVar:7888

gnomeAD: 0.00310 allelic freq.

CAID: n/a

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

PMID:39991341

Gene: ABCA4

Disease: Stargardt

Case#: Patient 1, Female, age 40

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0000007

CaseHPOFreeText: Patient diagnosed with STGD type 1, presenting with retinal pigment atrophy as well as other symptoms typical of STGD1 with reduced visual acuity. Patient daignosed at age 16.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Patient ABCA-4 gene sequenced via Sanger sequencing of all 50 exons, Splice variants were identified by synthesized cDNA from RNA isolation with RT-PCR analysis with exonic primers.

PreviouslyPublished: Variant 1 identified in association with retinal dystrophy in these PMC articles: 23982839, 25082829, 25082885, 28327576

Variant: NM_000350.3(ABCA4):c.859-9T>C, NM_000350.3(ABCA4):c.303-3C>G

ClinVar: 3249248, 859348

gnomAD total allele frequency: 0.005% of var . 1

CAID: n/a

SupplementalData: Fig 1: Minigene RNA analysis of splice variants. A: genomic region of exon 40 on ABCA-4. B: genomic regions of exons 39-41 to investigate specific variant:oncanonical splice site variant c.5714+5G>A Fig 2: overview of wild-type midigene splice constructs of ABCA-4 and locations of 47 different non canonical splice site variants Fig 3: Overview of splice defects from nine different non canonnical splice variants in ABCA-4 gene. Fig 4: percentages of normal ABCA-4 transcripts as a result of noncanonical splice variants using electrophoresis system analysis. Table 1: Non canonical splice variants and observed protein affects.

**Case#: ** Female, 35yo

FamilyInfo: Unremarkable

CasePresentingHPOs: HP:0000529 Progressive visual loss, HP:0030532 Visual acuity, HP:0007401 Macular atrophy

CaseHPOFreeText: 35-year-old woman presented with symptom of gradually progressive diminution of vision in both eyes since childhood. Patient gave no history of defective night vision.

CaseNotHPO n/a

GenoTypeMethod: n/a (optical coherence tomography (OCT))

PMID: 35973334

Gene: ABCA4

HGNC ID: 34

Case#: Female, family #5, Patient #20

DiseaseAssertion: STGD

FamilyInfo: Proband's sister presented with same clinical prognosis. Sister diagnosed with pattern dystrophy and photoaversion at age 57, with difficulty seeing at night. Sister has nuclear sclerotic and cortical cataracts in both eyes.

CasePresentingHPOs: HP:0000662, HP:0000603, HP:0000603, HP:0000493

CaseHPOFreeText: Proband presented with localized blur at age 62, (late onset) in her left eye. BVCA 20/20-3 and 20/20-2 at age 70. Also has macular lesions with stage 2 fundus flecks.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: p.N18681, IVS36:c.5196+1G>A

ClinVar: M2) 99067, M6) 99351

CAID: N/A

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case: Multiple individuals with the same GRIN2B variant (the mean age was 76 ± 11 SD years (Range: 38–101), the mean age at PD onset was 67 ± 12 SD years (Range: 32–94), and 421 patients (63%) were male).

Disease Assertion: Parkinson's disease

FamilyInfo: None

CasePresentingHPOs: HP:0001300

CaseHPOFreeText: Parkinson's disease

CaseNotHPOs: HP:0001250

CasePreviousTesting: Polymorphism genotyping on Sequenom iPLEX ® platform

PreviouslyPublished: No

Variant: rs7301328

ClinVarID: 129205

PMID: 32843395

Gene: ABCA4

Disease: Stargardt

Gene name

PMID: 30692068

Gene: GDAP1

HGNCID: 15968

for - gene-culture coevolution - paper - prepress - Cultural inheritance is driving a major transition in human evolution - author - Timothy M Waring - Zachary T Wood

for - gene-culture coevolution - definition - Evolutionary Transition in both Inheritance and Individuality (ETII) - authors - Timothy M Waring - Zachary T Wood - paper - Cultural inheritance is driving a transition in human evolution 2025