Case#: 30 year old female athlete

DiseaseAssertion: Subclinical hypertrophic cardiomyopathy

FamilyInfo: Her mother has HCM and the same ACTC1 gene change. Her grandmother and uncle on her mothers side died suddenly.

ParentalTesting: Her mother tested positive for the ACTC1 gene change and there isn't any information about the father.

CasePresentingHPOs: NR

CaseHPOFreeText: The patient did not have dizziness, fainting, trouble breathing or chest pain. Her heart muscle was not thickened.

CaseNotHPOs: NR

CaseNotHPOFreeText: The patient sometimes felt her heart beating unusually during exercise. A heart MRI showed small changes in her heart muscle and heart valve.

CasePreviousTesting: The patient had an ECG, heart ultrasound, heart monitor and heart MRI

Genotyping Method:Sanger sequencing was used to test the ACTC1 gene.

FunctionalAnalysis: NR

Variant: ACTC1 p.Val11Leu

Clinvar: 2947021

CAID: CA391633409

gnomAD: NR

AdditionalInfo: The patient continued playing competitive sports and had regular heart checkups.

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.

Case1: HCM patient-derived cell line UKEi070-A (demographics not reported in this paper) DiseaseAssertion: HCM

ParentalTesting: CasePresentingHPOs: HP:0001639 CaseHPOFreeText: CaseNotHPOs: CaseNotHPOFreeText: CasePreviousTesting: Genotyping Method: Not reported in this paper; it references a previously established patient-derived cell line. FunctionalAnalysis: The variant is reported to cause MYBPC3 protein haploinsufficiency in cardiomyocytes. In this study, TTL overexpression normalized cell hypertrophy in the HCM cell model. Variant: NM_000256.3:c.2308G>A (heterozygous; the paper reports the splice consequence as p.Asp770Serfs98X) ClinVar: 36604 CAID: gnomAD: NR AdditionalInfo: The paper uses patient-derived induced pluripotent stem cell cardiomyocytes; it does not provide the patient’s age, sex, or pedigree.

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

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 B, Case IV.2; 8-year-old male; diagnosed at age 6

DiseaseAssertion: Dilated cardiomyopathy (DCM)

FamilyInfo: Positive family history of sudden cardiac death (SCD). The proband's brother (IV.1) died at age 2 of SCD and renal failure. Both parents (III.1 and III.2) were asymptomatic heterozygous carriers of MYL3 c.106G>T. Two unaffected siblings were tested: IV.3 was wild-type and IV.4 was heterozygous (Fig. 1b; Supplementary Fig. S2b).

ParentalTesting: Both parents (III.1 and III.2) were confirmed heterozygous carriers of MYL3 c.106G>T by PCR and bidirectional Sanger sequencing, supporting autosomal recessive inheritance (Supplementary Genetic Findings; Fig. S2b).

CasePresentingHPOs: HP:0001644 (Dilated cardiomyopathy); HP:0000085 (Horseshoe kidney); HP:0005162 (Reduced left ventricular ejection fraction).

CaseHPOFreeText: DCM diagnosed at age 6; heart transplantation performed shortly after diagnosis. Clinical evaluation revealed horseshoe kidney, severe left ventricular dysfunction (LVEF 15–20%), moderate right ventricular dysfunction (TAPSE 9 mm), chamber cardiomegaly on coronary CT angiography, and rapid ventricular tachycardia on ECG (Main text, Family B; Supplementary Results, p. 6).

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR (no prior diagnostic genetic testing reported before the study's exome sequencing)

Genotyping Method: Exome sequencing identified the homozygous MYL3 c.106G>T (p.Glu36Ter) variant in the proband (IV.2). PCR and bidirectional Sanger sequencing validated the variant and confirmed segregation in the parents and two unaffected siblings (Supplementary Methods; Supplementary Genetic Findings; Fig. S2b).

FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA containing c.106G>T (p.Glu36Ter). Unlike wild-type MYL3 RNA, the mutant RNA failed to rescue the cardiac phenotype, with persistent cardiac edema, ventricular dysfunction, and atrial dilation (Fig. 2; Supplementary Methods; Supplementary Movie S7).

Variant: MYL3 NM_000258.2:c.106G>T (p. Glu36Ter); homozygous nonsense variant

ClinVar: NR

CAID: CA352499542

gnomAD: NR

AdditionalInfo: The authors classified the homozygous MYL3 c.106G>T (p.Glu36Ter) nonsense variant as pathogenic. The variant introduces a premature termination codon at amino acid 36. The proband was born to asymptomatic, consanguineous (first-cousin) parents of Bakhtiyari ancestry. Family segregation and zebrafish functional studies provide supporting evidence (Supplementary Results; Supplementary Genetic Findings; Supplementary Table S2).

Case#: Family C, Case VI.1; female; diagnosed at age 2.5 years; died at age 8

DiseaseAssertion: Unclassified cardiomyopathy

FamilyInfo: Family C has a positive family history of childhood-onset cardiomyopathy and sudden cardiac death. The affected individual (VI.1) was diagnosed with cardiomyopathy at age 2.5 years and died at age 8. Three maternal relatives (V.5, V.6, and V.8) are depicted as affected and deceased in the pedigree (Fig. 1C). Both parents (V.1 and V.2) were clinically unaffected heterozygous carriers of the MYL3 c.482-1G>A splice-acceptor variant. The genotype of VI.1 could not be confirmed because DNA was unavailable.

ParentalTesting: PCR and bidirectional Sanger sequencing confirmed that both parents (V.1 and V.2) were heterozygous carriers of MYL3 c.482-1G>A. Direct testing of the affected daughter (VI.1) was not possible because DNA was unavailable. Her homozygous genotype was therefore suspected but not confirmed (Fig. 1C; Supplementary Genetic Findings).

CasePresentingHPOs: HP:0001638 (Cardiomyopathy); HP:0001645 (Sudden cardiac death).

CaseHPOFreeText: Female diagnosed with unclassified cardiomyopathy at age 2.5 years; died of sudden cardiac death at age 8 (Family C, Fig. 1C).

CaseNotHPOs: NR (no patient-specific negative HPO findings confirmed for VI.1).

CaseNotHPOFreeText: The authors reported no evidence of muscle weakness by neurological examination or history among affected individuals from the three families; however, it is unclear whether this assessment specifically included VI.1.

CasePreviousTesting: NR (no prior genetic testing reported for VI.1).

Genotyping Method: Genetic analysis of the affected individual's mother (V.2) identified MYL3 c.482-1G>A. PCR and bidirectional Sanger sequencing validated the variant and confirmed both parents (V.1 and V.2) as heterozygous carriers. VI.1 was not directly genotyped because DNA was unavailable (Supplementary Genetic Findings; Fig. 1C and S2C).

FunctionalAnalysis: A minigene splicing assay in human HEK293FT cells demonstrated that MYL3 c.482-1G>A causes abnormal RNA splicing. The predominant outcome (~75%) was skipping of the 78-bp exon 5, producing an in-frame deletion (p.Gly161_Glu186del). A less frequent outcome (~25%) was deletion of the first nucleotide of exon 5, causing a frameshift (p.Gly161Valfs*4). Both outcomes are predicted to disrupt EF-hand domains. The authors note that the minigene assay may not fully reflect in vivo splicing frequencies (Supplementary Results, pp. 7–8; Fig. 2E–I).

Variant: MYL3 c.482-1G>A (rs727503300)

ClinVar: 164486

CAID: CA013932

gnomAD: NR MYL3 c.482-1G>A was not found in the gnomAD v4 (GRCh38) region results at chr3:46,860,813. Allele frequency not reported for this variant in the searched dataset.

AdditionalInfo: The affected individual (VI.1) died at age 8, and DNA was unavailable for direct genetic testing. Both clinically unaffected parents (V.1 and V.2) were confirmed heterozygous carriers of MYL3 c.482-1G>A, suggesting that VI.1 may have inherited the variant from both parents; however, her genotype remains unconfirmed. A minigene assay demonstrated that the variant disrupts RNA splicing, predominantly causing exon 5 skipping, with a less frequent frameshift-producing splicing event. These functional findings support a damaging effect of the variant but do not establish VI.1's genotype (Fig. 1C; Fig. 2E–I; Supplementary Genetic Findings and Minigene Assay Results).

Case#: Family A, Case III.7; 38-year-old female; diagnosed at age 26

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Positive family history of HCM and SCD. Mother (II.4), brother (III.8), uncle (II.7), and cousin (III.11) died of SCD at ages 55, 26, 57, and 24, respectively. The proband's three children (IV.3, IV.4, IV.5) were homozygous for the MYL3 variant but had normal echocardiograms at ages 18, 13, and 6.

ParentalTesting: Supplementary Table S2 reports parental testing supportive of PM3 (variants in trans). However, DNA was unavailable for the proband's deceased mother (II.4), and individual parental genotypes were not specified in the supplementary genetic findings.

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy); HP:0002094 (Dyspnea); HP:0001653 (Mitral regurgitation); HP:0001712 (Left ventricular hypertrophy)

CaseHPOFreeText: HCM diagnosed at age 26 following dyspnea. At age 38, echocardiography showed reverse-curvature HCM with asymmetric left ventricular hypertrophy involving anterior, anterolateral, and lateral segments; maximum wall thickness 22 mm; severe mitral regurgitation; LVEF 55%; E/e' ratio 16.4; resting LVOT gradient 9 and post-maneuver gradient 30. Holter monitoring showed no arrhythmias (Supplementary Results, pp. 5–6; Table S1; Fig. S1).

CaseNotHPOs: HP:0001324 (Muscle weakness)

CaseNotHPOFreeText: Neurological evaluation revealed normal muscle tone, strength 5/5 in upper and lower limbs, no distal or proximal muscle atrophy or fasciculations, and normal creatine phosphokinase levels.

CasePreviousTesting: Exome sequencing was performed; no rare, likely pathogenic variants in other cardiomyopathy-associated genes identified after filtering.

Genotyping Method: Exome sequencing identified the MYL3 variant; bidirectional Sanger sequencing validated the variant. Familial genotyping supported recessive inheritance (Fig. 1a).

FunctionalAnalysis: Zebrafish cmlc1 knockdown and rescue experiments were performed using human MYL3 RNA carrying c.170C>A (p.Ala57Asp). Mutant RNA showed partial phenotypic rescue but no statistically significant improvement in ventricular contractility compared with knockdown alone (Fig. 2a-d).

Variant: MYL3 NM_000258.2:c.170C>A (p.Ala57Asp); homozygous missense variant; rs139794067

ClinVar: 43121

CAID: CA013575

gnomAD: Allele frequency 0.000163 (0 homozygotes), as reported in Supplementary Table S2.

AdditionalInfo: Family A, Case III.7. Clinical characteristics and genetic findings described in the Results section (Fig. 1a and 1d-e). Functional experiments described in Fig. 2. The authors classified c.170C>A as a variant of uncertain significance (VUS).

Case#: Family #6; 36-year-old male

DiseaseAssertion: Arrhythmogenic right ventricular cardiomyopathy (ARVC); diagnosed according to the 2010 revised Task Force Criteria

FamilyInfo: Family #6. No informative segregation evidence specifically linking the MYL3 variant to ARVC was reported. The authors noted that family screening was incomplete or normal in other families, but did not specify which circumstance applied to Family #6.

ParentalTesting: NR

CasePresentingHPOs: HP:0006682 (PVCs)

CaseHPOFreeText: Symptomatic presentation; major right ventricular structural abnormality; minor ECG repolarization criterion; 1,181 ventricular ectopic beats on Holter monitoring; sustained ventricular arrhythmia (specific rhythm not reported).

CaseNotHPOs: HP:0001279 (Syncope); HP:0005162 (Abnormal left ventricular function)

CaseNotHPOFreeText: No cardiac syncope or left ventricular dysfunction reported. Absence of cardiac syncope does not necessarily exclude every form of syncope.

CasePreviousTesting: No pathogenic or likely pathogenic variants identified in established ARVC-associated genes (PKP2, DSG2, DSP, DSC2, JUP, TMEM43, PLN, SCN5A). Subsequent screening included nine sarcomere genes: ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1. The study used broad genetic testing, including whole-exome sequencing in a subset of probands; whether Family #6 underwent whole-exome sequencing was not specified.

Genotyping Method: Sarcomere-gene sequencing and deletion/duplication analysis through clinical cardiomyopathy panels, research-based next-generation sequencing panels, or whole-exome sequencing. The exact initial platform for Family #6 was not specified. Identified variants were confirmed by PCR amplification and Sanger sequencing.

FunctionalAnalysis: NR

Variant: MYL3 NM_000258.2:c.461G>A (p.Arg154His); missense variant; exon 4

ClinVar: 14062

CAID: CA013861

gnomAD: MYL3 c.461G>A (p.Arg154His), GRCh38: 3-46859495-C-T. gnomAD v4: Exome AF = 0.00003557; Genome AF = 0.00001971; Total AF = 0.00003408. European (non-Finnish): AC = 52, AF = 0.00004407. https://gnomad.broadinstitute.org/variant/3-46859495-C-T?dataset=gnomad_r4

AdditionalInfo: Murray et al. (2018), Tables 1 and 2, Family #6. The MYL3 variant was classified as likely pathogenic (LP) according to ACMG criteria, with a PolyPhen-2 score of 0.861. The proband met criteria for definite ARVC, with no reported left ventricular dysfunction. Although the variant was rare and computationally predicted to be damaging, the authors emphasized that evidence demonstrating a causal relationship between sarcomere variants and ARVC remained insufficient. No direct functional analysis of this variant was performed in the study.

Case#: Female, 4 months, Swedish

DiseaseAssertion: dilated cardiomyopathy

FamilyInfo: Strong family history of DCM and faily history of SCD due to DCM. Maternal grandfather had enlarged left ventricle.

ParentalTesting:

CasePresentingHPOs: HP:0005162, HP:0031295, HP:0001653,

CaseHPOFreeText: enlarged left ventricle,

CaseNotHPOs:HP:0011947

CaseNotHPOFreeText: circulatory collapse

CasePreviousTesting: NR

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant: NM_001276345.2:c.548G>A

ClinVar:43649

CAID: CA004727

gnomAD:NR

AdditionalInfo: During cardiac catheterization, cardiac resuscitation due to circulatory collapse was needed.

Case1: Male, Infant, Tunisian

DiseaseAssertion: infantile-onset HCM and mitral valve dysplasia

FamilyInfo: Family with consanguinity in which four children had died before one year of age. The father (37 years old) and mother (27 years old) of the proband are consanguineously related. Two infants (VI:1 and VI:2) died at less than 30 days of age from cardiorespiratory arrest, and two (VI:3 and VI:4, proband) of them displayed abnormal cardiac findings on chest roentgenogram. While all four children displayed hepatomegaly and general hypotonia, VI:3 and VI:4 had a marked increase in heart size and died from refractory cardiogenic shock. The status of the MYL2 allele in siblings is unknown. The proband (fs/fs) was homozygous for the MYL2-fs allele while the parents were found to be heterozygous (fs/wt) carriers. The father (37 years old) and mother (27 years old) of the proband are consanguineously related, were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram

ParentalTesting: Homozygous variant in the proband and that the parents are heterozygous carriers using Sanger DNA sequencing of the genomic region. Father (37 years old) and mother (27 years old) were asymptomatic from a cardiac standpoint and had normal cardiac anatomy and function as evaluated by an echocardiogram

CasePresentingHPOs: HP:0200128, HP:0001653, HP:0002092, HP:0001639, HP:0002240

CaseHPOFreeText: Showed a rapid decline in health and was treated for various periods in neonatal intensive care units. The patient also displayed severe mitral valve regurgitation with abnormal thickening of the mitral valve leaflets and pulmonary arterial hypertension. Post-mortem examination of the proband’s heart confirmed severe biatrial dilatation, significant biventricular hypertrophy with small ventricular cavities and severe mitral valve dysplasia

CaseNotHPOs: NR

CaseNotHPOFreeText: no gross developmental defects

CasePreviousTesting: No prior genetic testing reported before exome sequencing

Genotyping Method: Performed exome sequencing on the proband. Exome libraries were constructed using the Agilent SureSelectQXT Target Enrichment System for Illumina Multiplexed Sequencing Protocol (Agilent Technologies, CA). DNA libraries were captured with the Agilent Clinical Research Exome Kit. Paired-end 150 base pair reads were generated for exome-enriched libraries sequenced on the Illumina HiSeq 4000 to a targeted depth of 100× coverage

FunctionalAnalysis: Functional analysis performed. Immunohistochemical analysis of MYL2 expression in the proband’s ventricular myocardium shows a remarkable reduction in the expression of MYL2 as compared to control. Also, MYL2 mRNA was detected in the ventricle of the proband by RT-PCR. This suggests that the frameshift variant adversely affects the levels of MYL2 protein in the proband. Using immunoblot analysis, we observed that overexpression of the MYL2-fs variant was significantly reduced compared to stop-gain variants and the missense variant. When the H9c2 cells were treated with MG-132 after transfection with the MYL2-fs construct, the GFP signal corresponding to MYL2-fs was recovered. The in vitro experiments indicate that the MYL2-fs variant is not stable and that proteasome-mediated degradation of the translated product plays a key role in the instability of the protein. The overexpression of the fs variant identified in our proband or the MYL2-G162R missense variant failed to rescue the phenotype. Results reported in Figures 2, 3, and 4.

Variant: NM_000432.3:c.431_432delCT

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: 4 siblings who died before 1 year of age but MYL2 genotyping was only confirmed in the proband (VI:4)

Case1: Male, 37 years old, Colombian

DiseaseAssertion: asymmetric septal hypertrophic cardiomyopathy

FamilyInfo: During genetic assessment, a family history of hypertrophic cardiomyopathy (HCM) was detected. The patient’s mother had HCM and died at the age of 66; two living brothers have HCM (51 and 60 years of age). In addition, two of his brothers under the age of 35 died suddenly, two more brothers died from an unknown cause before the age of 5, and yet another brother is being examined for possible heart disease. Findings indicated a dominant inheritance pattern for HCM in this family. Pedigree shown in Figure 2.

ParentalTesting: NR

CasePresentingHPOs: HP:0001639, HP:0001663, HP:0001962, HP:000209, HP:0002315

CaseHPOFreeText: At the age of 25, his symptomatology started, including intense fatigue and mild thoracic pain due to physical activity. At the age of 32, an echocardiogram revealed asymmetric septal hypertrophic cardiomyopathy. The thickness of the interventricular septum was 19.5 mm in the basal third, 22 mm in the middle third, and 23 mm in the apical third, and ventricular tachycardia was also present. Alcohol septal ablation was performed. However, ventricular tachycardia and disabling symptoms persisted, so he required an implantable cardioverter-defibrillator at the age of 35. A routine echocardiogram at the age of 36 yielded the following findings: an LV of normal size, mild hypertrophy of the septum, normal systolic function, and diastolic dysfunction with slow LV relaxation. The patient still suffers dyspnea during physical effort and occasionally thoracic pain with palpitations

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: A molecular panel for HCM including 17 genes was performed using next-generation sequencing. Sanger sequencing chromatogram focusing on the targeted region including the variation

FunctionalAnalysis: NR

Variant: NM_000432.3:c.260G>C

ClinVar: 43461

CAID: CA009968

gnomAD: NR

AdditionalInfo: NR

PMID: 33139982

Gene: MYL2

HGNC ID: 7583

Case#: Japanese female

DiseaseAssertion: Mild cardiac hypertrophy and asymmetric septal hypertrophy with myocardial hypertrophy increasing.

FamilyInfo: mother and grandmother showed phenotype. Probands mother has the Arg92Trp mutation of TNNT2.

ParentalTesting:not reported

CasePresentingHPOs: HP:0001670

CaseHPOFreeText: not reported

CaseNotHPOs:not reported

CaseNotHPOFreeText:not reported

CasePreviousTesting: DNA analysis

Genotyping Method: Patients with familial HCM

FunctionalAnalysis:not reported

Variant:NM_001276345.2:c.107A>T

ClinVar:not reported

CAID:CA344207376

gnomAD:not reported

AdditionalInfo: pedigree and phenotype associated with Family C.

Case#: Female, 6 months

DiseaseAssertion: Dilated cardiomyopathy

FamilyInfo: Mother was age 40 at time of birth, which is a high-risk factor for birth defects

ParentalTesting:

CasePresentingHPOs: HP:0031664, HP:0010438, HP:0005162

CaseHPOFreeText: blood pressure of the four limbs was "92/44 mmHg at the right upper limb, 96/58 mmHg at the left upper limb, 101/60 mmHg at the right lower limb, and 103/54 mmHg at the left lower limb." Enlarged heart boundaries. Shifted apex.

CaseNotHPOs: HP:0000975

CaseNotHPOFreeText: decreased milk consumption

CasePreviousTesting: NR

Genotyping Method: genomic sequencing.

FunctionalAnalysis: NR

Variant: NM_001276345.2:c.548G>A

ClinVar:43649

CAID:CA004727

gnomAD: NR

AdditionalInfo:

Case#: Male, 17

DiseaseAssertion: hypertrophic cardiomyopathy

FamilyInfo: All family members were asymptomatic, with normal TTE and ECG, with no evidence of VH.

ParentalTesting:

CasePresentingHPOs: HP:0001639, HP:0001279, HP:0001670, HP:0032092, HP:0031295

CaseHPOFreeText: diastolic type II dysfunction,

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: genetic analysis of the proband was performed through direct sequencing of the three sarcomere genes: MYH7, MYBPC3 and TNNT2

Genotyping Method: Sanger Sequencing

FunctionalAnalysis: NR

Variant: NR

ClinVar:NR

CAID: NR

gnomAD: NR

AdditionalInfo: underwent clinical and cardiovascular examination, including a 12-lead electrocardiogram (ECG), transthoracic echocardiography (TTE) and 24-hour Holter monitoring. TNNT2 sequenced, but not reported.

Case#: Patient 1, individual II.1 (Fig. 2A); 22-year-old Salvadoran female

DiseaseAssertion: Restrictive cardiomyopathy (RCM) with advanced heart failure

FamilyInfo: Patient denied a family history of cardiomyopathy, although supporting records were unavailable. Her mother (I.2) was clinically unaffected at age 45 and heterozygous for both MYL3 p.Glu143Lys and MYL2 p.Gly57Glu. Other family members were unavailable for evaluation (Fig. 2A; Table I).

ParentalTesting: Mother (I.2) was confirmed heterozygous for MYL3 c.427G>A (p.Glu143Lys) and MYL2 c.170G>A (p.Gly57Glu). Paternal testing was not reported.

CasePresentingHPOs: HP:0012764 (Orthopnea); HP:0004749 (Atrial flutter); HP:0031295 (Left atrial enlargement); HP:0030718 (right atrial enlargement)

CaseHPOFreeText: Worsening fatigue and exertional dyspnea over 12 months, paroxysmal nocturnal dyspnea, palpitations, NYHA Class III–IV heart failure, and ascites suggestive of congestive hepatopathy. Echocardiography showed severe biatrial enlargement and advanced left ventricular diastolic dysfunction with preserved systolic function. Additional findings included myocardial fibrosis and myofiber disarray on biopsy.

CaseNotHPOs: NR

CaseNotHPOFreeText: At initial presentation, patient denied dizziness, syncope, and lower-extremity edema. No S4 heart sound was detected. Recurrent syncope developed later.

CasePreviousTesting: Targeted sequencing of eight sarcomere genes (ACTC, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1). Genome-wide analysis was not reported. An additional heterozygous MYL2 variant, c.170G>A (p.Gly57Glu), was identified (ClinVar Variation ID: 43458; CAID: CA009910).

Genotyping Method: Sequencing of coding exons and intron–exon boundaries of MYL3 and seven additional sarcomere genes, performed by a commercial CLIA-certified laboratory (Correlagen Diagnostics, Inc.). The specific sequencing platform was not reported.

FunctionalAnalysis: NR

Variant: MYL3 NM_000258.2:c.427G>A (p.Glu143Lys); homozygous

ClinVar: 14063

CAID: CA013774

gnomAD: MYL3 c.427G>A (p.Glu143Lys). Highest reported ancestry-specific allele frequency: 0.0002333 (0.02333%) in the Admixed American population (AC = 14). Overall AF (exomes): 0.000008209; AF (genomes): 0.00001314; AF (total): 0.000008674. https://gnomad.broadinstitute.org/variant/3-46859529-C-T?dataset=gnomad_r4.

AdditionalInfo: Patient developed recurrent syncope and received an implantable cardioverter-defibrillator. She underwent orthotopic heart transplantation six months after RCM diagnosis. Authors considered the homozygous MYL3 and heterozygous MYL2 variants likely contributors to disease, although their individual contributions were not established. Clinical and family findings are reported in Patient 1, Figure 2A, and Table I.

Case1: Female, 23 years old, ethnicity not stated

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM)

FamilyInfo: Mother, brother, and sister carry the same MYL2 mutation. Mother has phenotypic HCM without scar or high-risk features for sudden cardiac death. Sister and brother remain phenotypically negative with yearly imaging.

ParentalTesting: Maternal testing confirmed — mother carries the same MYL2 mutation and has phenotypic HCM. Paternal testing not reported.

CasePresentingHPOs: HP:0011675, HP:0001279, HP:0001962, HP:0004756

CaseHPOFreeText: During a sprinting drill, she developed a 42-second episode of polymorphic VT with spontaneous termination. The ambulatory rhythm monitoring showed a ~4% premature ventricular contraction (PVC) burden without sustained or nonsustained VT. CPET 2 demonstrated monomorphic nonsustained VT at peak exertion. Given exercise-induced polymorphic VT, she underwent placement of a subcutaneous implantable cardioverter-defibrillator (ICD) for secondary prevention. In the emergency department, high-sensitivity troponin rose from 105 to 303 ng/L. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis

CaseNotHPOs:HP:0100749, HP:0002094, HP:0031972, HP:0001714

CaseNotHPOFreeText: Normal LV size and function on echocardiography. Normal strain. Repeat cardiac MRI showed complete resolution of LGE. Normal biventricular size, thickness, and function without LGE or scar on third MRI. No sustained VT/VF after ICD placement. Normal complete blood count and basic metabolic panel. Coronary CT angiography unremarkable.

CasePreviousTesting: She underwent coronary computed tomography angiography to rule out ischemia and anomalous coronary origins, which was unremarkable. Cardiac magnetic resonance imaging (MRI) demonstrated normal LV function with subepicardial late gadolinium enhancement (LGE) in the basal to mid inferolateral wall, concerning for acute myocarditis. Follow-up transthoracic echocardiography revealed normal LV size and function with normal strain, and repeat cardiac MRI showed complete resolution of LGE. She underwent maximal cardiopulmonary exercise testing (CPET), exercising for 13 minutes and 15 seconds, achieving 15 METs with a VO2 max of 40.4 mL/kg/min, which demonstrated frequent PVCs without nonsustained ventricular tachycardia (VT). Normal complete blood count and basic metabolic panel, aspartate aminotransferase, 38 U/L, alanine aminotransferase, 38 U/L, magnesium 2.2 mg/dL, thyroid-stimulating hormone, 1.96 μIU/mL, hemoglobin A1c, 5.8%.

Genotyping Method: Comprehensive genetic testing identified a pathogenic MYL2 variant.

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.4:c.173G>A

ClinVar: 14067

CAID: CA009915

gnomAD: 12:111352091 C / T, chr12-110914287-C-T

AdditionalInfo: NR

Case1: Male, Infant, ethnicity not stated

DiseaseAssertion: congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy

FamilyInfo: The father was a healthy 20-yr old with no particular medical concerns, and there was no family history of neuromuscular or genetic disorders on either side. Both parents confirmed as heterozygous carriers of the MYL2 c.188del variant by Sanger sequencing

ParentalTesting: Both parents were confirmed as heterozygous carriers of MYL2 c.188del p.(Asn63Metfs7) by Sanger sequencing. Father confirmed as heterozygous carrier of NEB c.25435C>T p.(Gln8479)

CasePresentingHPOs: HP:0001290, HP:0001252, HP:0001640, HP:0001638, HP:0001639

CaseHPOFreeText: Newborn exam revealed normal first and second heart sound with gallop rhythm and palpable liver at the right costal margin, as well as generalized hypotonia and diminished reflexes. Echocardiogram was performed at 11 d of age and revealed patent foramen ovale with left to right shunt and right atrial enlargement. At age 5 mo, the proband was admitted to hospital in decompensated heart failure and intubated on inotropic support. Echocardiography revealed left ventricular dilatation, mild to moderate mitral valve regurgitation, and left atrial enlargement, with left ventricular function moderately to severely decreased with shortening fraction of 12% and ejection fraction of 23%. A vastus lateralis biopsy performed at 5 mo of age because of persistent muscle weakness and hypotonia revealed variability in fiber size with checkerboard pattern of 1:1 ratio of type 1 and type 2 fibers exhibiting hypotrophy of type 1 fiber size in comparison to the type 2 fibers. high lactate level (7.8 mmol/L)

CaseNotHPOs: NR

CaseNotHPOFreeText: Gomori trichrome–stained light micrographs and electron microscopy (EM) showed no evidence of ragged red fiber or nemaline rods, and oxidative stains revealed no evidence of cores, targetoid, or target fibers. Normal serum creatine kinase level. Normal birth weight, length, and head circumference. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Genetic testing for POLG and Noonan syndrome genes normal

CasePreviousTesting: Genetic testing was performed for DNA polymerase γ, catalytic subunit (POLG) and Noonan syndrome genes (PTPN11, SOS1, KRAS, RAF1, BRAF, MAP2K1, MAP2K2, and HRAS), all of which were normal. There was no histopathologic evidence of Pompe disease and GAA enzyme-level testing was normal. Muscular dystrophy was considered unlikely given the histopathologic findings and normal serum creatine kinase level.

Genotyping Method: Next-generation sequencing was performed by the Laboratory for Molecular Medicine (LMM) of Partners Healthcare Personalized Medicine using the Agilent SureSelect Design process. The gene panel utilized an all exon approach for 43 genes of interest for neuromuscular and cardiac conditions by targeting coding exons with bait out to coding sequence (CDS) ±65 bases. The complete coding regions of all genes were sequenced to average depth of 316 reads

FunctionalAnalysis: No functional analysis of the variant was performed

Variant: NM_000432.3:c.188del

ClinVar: NR

CAID: UnregisteredVariant

gnomAD: NR

AdditionalInfo: This case also has a heterozygous pathogenic NEB variant c.25435C>T p.(Gln8479*) inherited from the father, classified as pathogenic but considered unlikely to be a significant contributor to disease as no second NEB allele was identified.

Case: Female, 19 y.o., ethnicity unknown.

DiseaseAssertion: VWD2N

FamilyInfo: Proband has one older symptomatic sister who shares an identical compound heterozygous genotype, presenting with a mild bleeding tendency, reduced FVIII activity (20-30%), and severely reduced FVIII binding (<2%). The family features one younger unaffected sister who tested negative for both variants, and an unaffected carrier mother. Both parents had normal factor VIII, and there was no male relative with reduced factor VIII or bleeding symptoms.

ParentalGenotype(s): Mother is heterozygous for the c.2561G>A (p.R854Q) variant, negative for the c.2402G>A (p.S801N) variant, and has normal baseline factor VIII levels, confirming the sisters' variants are in trans. Father unavailable/not tested.

CasePresentingHPOs: HP:0004846 (Prolonged bleeding after surgery), HP:0003645 (Prolonged partial thromboplastin time).

CaseHPOFreeText: Index patient experienced bleeding complications following wisdom tooth surgery. Factor VIII binding activity is reduced at 32%. Reduced coagulation factor VIII activity (30%). Prolonged activated partial thromboplastin time (aPTT) of 37 seconds.

CaseNOTHPOs: HP:0001873 (Thrombocytopenia), HP:0012147 (Reduced quantity of von Willebrand factor), HP:0030130 (Impaired von Willebrand factor collagen binding activity).

CaseNOTHPOFreeText: Normal vWF antigen (vWF:Ag) levels (101%), normal vWF activity (116%), normal vWF-collagen-binding activity (104%), normal vWF multimer distribution structures, normal hemoglobin level (128 g/L), and normal Prothrombin Time (PT/QUICK) of 83%.

CasePreviousTesting: Siblings did not carry any known mutations in the F8 gene or the LMAN1 and MCFD2 genes (which encode for endoplasmic reticulum carrier proteins of coagulation factors V and VIII).

GenotypingMethod: Direct sequence analysis of VWF exons 18-20.

PreviouslyPublished: NA.

Gene: VWF

HGNCID: HGNC:12726

Variant: Heterozygous c.2561G>A (p.R854Q) and heterozygous c.2402G>A (p.S801N).

HGVS: (1) NM_000552.5:c.2561G>A (p.Arg854Gln) (2) NM_000552.5:c.2402G>A (p.Ser801Asn)

ClinVarID: (1) 296 (2) NA

CAID: (1) NA (2) CA383522023

gnomAD: (1) MAF of 0.005974 in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4

(2) MAF of 0.00001098 in the South Asian population https://gnomad.broadinstitute.org/variant/12-6044331-C-T?dataset=gnomad_r4

Case#: Eldest child, female, age at diagnosis and onset are unknown, age at treatment is 6, age at report is 11 DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0000280, HP:0008800, HP:0010501, HP:0006467, HP:0001659, HP:0001653, HP:0001634 (Coarse facial features, Limited hip movement, Limited shoulder movement, Limitation of knee mobility, Aortic regurgitation, Mitral regurgitation, Mitral valve prolapse) CaseHPOFreeText: Corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

Case#: Youngest child, Female, age at diagnosis and onset are unknown, age at treatment is 4 months, age at report is 5 years, 4 months DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: N/A CaseHPOFreeText: Mild corneal clouding, this study is to examine the efficacy of enzyme replacement therapy at different stages of teh disease, and it is assumed this patient is not yet old enough to have develped symptoms CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

Case#: Middle child, Male, age at diagnosis and onset are unknown, age at treatment is 2.5 years, age at report is 7.5 years DiseaseAssertion: MPS1 FamilyInfo: All 3 cases are siblings CasePresentingHPOs: HP:0001634, HP:0001653 (mitral valve prolapse, mitral regurgitation) CaseHPOFreeText: Mild corneal clouding CaseNotHPOs: N/A CaseNotHPOFreeText: N/A CaseEnzymeAssay: N/A CaseUrineGAGs: N/A CaseERT: Yes CaseBMT: Don't know Variant1: p.Leu490Pro Variant1ClinVarID: 11919 Variant1CAID: Variant2: p.Leu490Pro Variant2ClinVarID: 11919 Variant2CAID: AdditionalVariants: N/A ParentalGenotype: N/A PreviouslyPublished N/A

CasePT-104: United States

CasePresentingHPOs: HP:0001639 (Hypertrophic cardiomyopathy)

HPOsFreeText: N/A

CaseNotHPOs: HP:0001650, HP:0001658 (Aortic valve stenosis, Myocardial infarction)

NotHPOsFreeText: N/A

CaseAddInfo:

CaseGenotypingMethod: DNA was collected from the participants using blood samples. 18 genes suspected on contributing to HCM were targeted and sequenced. The variants were then located and filtered for pathogenicity.

Variant: NM_000257.3:c.4399C>G (p.Leu1467Val)

ClinVar: 43015 https://www.ncbi.nlm.nih.gov/clinvar/variation/43015/

gnomAD: South Asian 1.111e-3, Overall 1.352e-4 https://gnomad.broadinstitute.org/variant/14-23886482-G-C

Case18: Male, 4 yr diagnosis, 5.2 yr report

HPOsFreeText: FVC z-score sitting -1.41 (82% pred), FVC z-score supine -1.96 (76% pred), 97% MRC Scale, 677 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case5: Male, 0.8 yr onset, 2.3 yr diagnosis, 9.5 yr report

HPOsFreeText: FVC z-score sitting -1.53 (82% pred), FVC z-score supine -1.71 (80% pred), 98% MRC Scale, 550 CK U/l, 15.4 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case29: Female, 6.5 yr onset, 11.6 yr diagnosis, 12.7 yr report

CasePresentingHPOs: HP:0001371 (Contractures)

HPOsFreeText: FVC z-score sitting -2.36 (73% pred), FVC z-score supine -2.89 (67% pred), 79% MRC Scale, 776 CK U/l, 8.4 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case20: Male, 14 yr diagnosis, 15.2 yr report

HPOsFreeText: FVC z-score sitting 3 (135% pred), FVC z-score supine 1.72 (120% pred), 1409 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case16: Male, 12 yr onset, 8 yr diagnosis, 14.6 yr report

HPOsFreeText: FVC z-score sitting -2.43 (71% pred), 82% MRC Scale, 1808 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case25: Male, 2.7 yr onset, 3.5 yr diagnosis, 5.9 yr report

HPOsFreeText: FVC z-score sitting 0.34 (104% pred), FVC z-score supine 0.04 (100% pred), 87% MRC Scale, 908 CK U/l, 2.8 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case21: Male, 16 yr diagnosis, 17.1 yr report

HPOsFreeText: FVC z-score sitting 1.29 (115% pred), FVC z-score supine -0.25 (97% pred), 1506 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case1: Male, 0.5 yr onset, 2.5 yr diagnosis, 10.04 yr report

CasePresentingHPOs: HP:0001371 (Contractures)

HPOsFreeText: Wheelchair used, FVC z-score sitting -0.25 (97% pred), FVC z-score supine -1.12 (87% pred), 65% MRC Scale, 530 CK U/l, 9.1 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No respiratory support

Case9: Male, 2 yr onset, 1 yr diagnosis, 6.6 yr report

HPOsFreeText: FVC z-score sitting -0.97 (89% pred), FVC z-score supine -1.4 (84% pred), 94% MRC Scale, 763 CK U/l, 11 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case9: Male, 5 yr onset, 10.8 yr diagnosis, 10.8 yr report

HPOsFreeText: FVC z-score sitting 0.2 (102% pred), FVC z-score supine -0.29 (97% pred), 97% MRC Scale, 588 CK U/l, 11.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case19: Male, 13.1 yr diagnosis, 13.1 yr report

HPOsFreeText: FVC z-score sitting -0.69 (92% pred), FVC z-score supine -1.77 (80% pred), 100% MRC Scale, 614 CK U/l, Deficent GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used, No respiratory support

Case7: Male, 1 yr onset, 2 yr diagnosis, 13.7 yr report

CasePresentingHPOs: HP:0002650 (Scoliosis)

HPOsFreeText: Respiratory support at night, FVC z-score sitting -4.08 (54% pred), FVC z-score supine -5.4 (39% pred), 87% MRC Scale, 548 CK U/l, 17.9 GAA activity (nmol/h/mg)^h from cultured fibroblasts

NotHPOsFreeText: No wheelchair used

Case5: Female, Caucasian, United States, 2 months onset and diagnosis, 0.4 years report

CasePresentingHPOs: HP:0011968, HP:0011469, HP:0012378, HP:0004347, HP:0010453 (Feeding difficulties, Nasal regurgitation, Fatigue, Weakness of muscles of respiration, Pelvic bone asymmetry)

HPOsFreeText: Difficulty in lying supine while eating, sleeping and self-limited gasping episodes was observed, PT evaluation showed mild consistent asymmetry with increased lateral head tilt to the right, Tendency towards flexion/abduction/external rotation positioning of lower extremities was noted, Slight lateral thigh grooves reflected early IT band tightness with decreased posterior weight shift and propping on forearms in prone, AIMS score was at 10th percentile for chronological age and 25th to 50th percentile for corrected age, ALT 27 U/L (Normal 5–40 U/L), AST 36 U/L (Normal 15–41 U/L), ALP 352 U/L (Normal 24–170 U/L), Urinary Glc4 4.1 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

CaseNotHPOs: HP:0002033, HP:0002015, HP:0004323, HP:0003808 (Poor suck, Poor swallowing, Abnormality of body weight, Abnormal muscle tone)

NotHPOsFreeText: CK levels, ECG, and ECHO have consistently been within normal limits, Had normal passive ranges of motion and appropriate weight bearing through lower extremities in supported standing

Case4: Female, Caucasian, United States, 1 month onset, 6 months diagnosis, 1.1 years report

CasePresentingHPOs: HP:0003236, HP:0012378, HP:0006589, HP:0003725 (Increased serum CK, Fatigue, Flaring of lower rib cage, Firm muscles)

HPOsFreeText: HyperCKemia present in the first month (505 IU/L; Normal 30–279 IU/L) but normalized spontaneously at 4 months (188 IU/L), PT assessment revealed subtle motor signs including preferred position of ring sitting with hips in flexion/abduction/external rotation and bilateral IT band tightness, Imbalanced trunk flexion, Decreased use of abdominals and excessive use of spinal extension, Asymmetry was noted in reaching objects in prone and weight shifting with lateral flexion and shortening on the left at the neck and trunk, AIMS score was at the 25th percentile and GMFM was 22.14%, Urinary Glc4 4.8 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

CaseNotHPOs: HP:0003690 (Limb muscle weakness)

NotHPOsFreeText: She had no head lag when pulled to sit and the ability to transfer objects and bring them to midline

Case1: Male, Caucasian, United States, Birth onset

CasePresentingHPOs: HP:0008872, HP:0002100, HP:0001508, HP:0008947, HP:0001655, HP:0003236, HP:0200136, HP:0001290, HP:0002835, HP:0002194 (Feeding difficulties in infancy, Recurrent aspiration pneumonia, Poor weight gain, Infantile muscular hypotonia, Patent foramen ovale, Increased serum CK, Oropharyngeal dysphagia, Low muscle tone, Aspiration, Delayed gross motor development)

HPOsFreeText: HyperCKemia was present since the early neonatal period (378 IU/L, day 8 of life; N: 60–305 IU/L), ERT at a dose of 20 mg/kg every 2 weeks was initiated at age 1 month, CK levels were normalized on ERT by age 4 months (80 IU/L), Flexion/abduction/ external rotation positioning of lower extremities, iliotibial (IT) band tightness, lack of independent sitting, AIMS score between 10th and 25th percentile, GMFM at 23.16%, At age 23 months, he had achieved significant motor milestones; started sitting with support at 10 months and without support at 12 months, pulled to stand at 12 months, walked at 15 months and could feed himself with an immature pincer grasp. Swallow study was normal, ALT 26 U/L (Normal 5–40 U/L), AST 45 U/L (Normal 15–41 U/L), ALP 211 U/L (Normal 24–170 U/L), Urinary Glc4 3.7 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

CaseNotHPOs: HP:0011675, HP:0002910 (ECG abnormality, Elevated hepatic transaminases)

NotHPOsFreetext:

CaseAddInfo: Older brother of Patient 2, Late-Onset Pompe Disease

Case2: Male, Caucasian, United States, Birth onset

CasePresentingHPOs: HP:0001290, HP:0200136, HP:0002033, HP:0003236, HP:0001655, HP:0002058, HP:0002194, HP:0002421, HP:0000467, HP:0002015 (Generalized hypotonia, Oral-pharyngeal dysphagia, Poor suck, Increased serum CK, Patent foramen ovale, Myopathic face, Delayed gross motor development, Poor head control, Neck muscle weakness, Dysphagia)

HPOsFreeText: hyperCKemia at 435 IU/L on day of life 4, Patent foramen ovale detected at birth by ECHO but resolved spontaneously, PT evaluation at age 2 months revealed flexion/abduction/external rotation positioning of lower extremities with tightness bilaterally in hip flexors, hamstrings, and IT bands, Had a tendency to remain on toes when held in supported standing with additional support required for weight bearing through lower extremities, Had difficulty lifting his head in prone, with asymmetric head lift to 45 degrees, and an inability to maintain head in midline when supine, AIMS score at age 2 months was between 10–25th percentile, ALT 41 U/L (Normal 5–40 U/L), AST 33 U/L (Normal 15–41 U/L), ALP 239 U/L (Normal 24–170 U/L), Urinary Glc4 4.5 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

CaseNotHPOs: HP:0011016 (Abnormality of urine glucose concentration)

NotHPOsFreeText:

CaseAddInfo: Younger brother of Patient 1, Late-Onset Pompe Disease

Case7: Female, Caucasian, United States, 6 months diagnosis, 8 months report

CasePresentingHPOs: HP:0001643, HP:0006699, HP:0006682, HP:0003722, HP:0008969 (Patent ductus arteriosus, Premature atrial contractions, Premature ventricular contractions, Neck flexor weakness, Leg muscle stiffness)

HPOsFreeText: At 6 months head lag during pull to sit was noted, Had predominant overall flexion position of lower extremities with a tendency towards hip flexion/abduction/external rotation, with lateral thigh grooves suggestive of bilateral IT band tightness, AIMS score was between 10th and 25th percentile for chronological age and 50th percentile for her corrected age adjusted for prematurity while GMFM score was 16.55%, ALT 37 U/L (Normal 5–40 U/L), AST 53 U/L (Normal 15–41 U/L), ALP 174 U/L (Normal 24–170 U/L)

CaseNotHPOs: HP:0003236, HP:0001712, HP:0001290 (Increased serum CK, Left ventricular hypertrophy, Decreased muscle tone)

NotHPOsFreeText: Other evaluations including pulmonary, speech, and swallow were normal

Case6: Male, Caucasian, United States, 1 month onset, 6 months diagnosis, 8 months report

CasePresentingHPOs: HP:0003236, HP:0001655, HP:0003701, HP:0006589, HP:0003093, (Increased serum CK, Patent foramen ovale, Proximal muscle weakness, Flaring of lower rib cage, Limited hip extension,

HPOsFreeText: HyperCKemia was noticed in the first month (438 U/L; Normal 60–305) but normalized spontaneously by age 6 months, flexion/abduction/external rotation positioning of lower extremities and with bilateral IT band tightness was revealed at the same time, also had decreased active use of abdominal oblique muscles with a lack of active trunk rotation, Decreased active use of lower abdominal muscles with inability to achieve a posterior pelvic tilt in supine, AIMS score was at 1st percentile for age and GMFM was at 12.3%, ALT 30 U/L (Normal 5–40 U/L), AST 90 U/L (Normal 15–41 U/L), ALP 249 U/L (Normal 24–170 U/L), Urinary Glc4 2.6 mmol/mol creatinine (Normal ≤8.3 mmol/mol creatinine)

CaseNotHPOs: HP:0001712, HP:0001290 (Left ventricular hypertrophy, Decreased muscle tone)

NotHPOsFreeText: Other evaluations including cardiac, pulmonary, speech, and swallow were normal

Case1: Female, 55 years report, 25 years onset, Brazil, African

CasePresentingHPOs: HP:0003325, HP:0003236, HP:0003148, HP:0100284, HP:0011807, HP:0003326, HP:0008994, HP:0002527, HP:0003551, HP:0002015, HP:0000822, HP:0000819, HP:0003119, HP:0003707, HP:0003391, HP:0003327, HP:0001315, HP:0002515, HP:0010546 (Limb-girlde muscle weakness, Increased serum CK, Elevated serum acid phosphatase, EMG: myotonic discharges, Type 1 muscle fiber atrophy, Myalgia, Proximal muscle weakness in lower limbs, Falls, Difficulty climbing stairs, Dysphagia, Hypertension, Diabetes mellitus, Dyslipidemia, Calf muscle pseudohypertrophy, Gowers sign, Axial muscle weakness, Reduced deep tendon reflexes, Waddling gait, Muscle fibrillation)

HPOsFreeText: Serum CK 1467 U/L (normal: ≤ 200U/L), NaG/AaGIA ratio 40.4, %INH 87.2, GAA activity 4.2% from dried blood spot, Falls occurring mainly when walking for long distances, Normal Mini-Mental State Examination score (27/30), Mild symmetrical weakness in proximal muscles in the lower limbs (Medical Research Council grade 4), Needle electromyography revealed motor unit potentials with low amplitude and short duration in the iliopsoas muscle associated with fibrillation and short myotonic discharge potentials in lumbar paraspinal muscles

CaseNotHPOs: HP:0001270 (Motor delay)

NotHPOsFreeText: Muscle biopsy with the absence of vacuolar myopathy

CaseAddInfo: Late-Onset Pompe Disease, One sister diagnosed with LOPD based on low GAA activity and shared genetic variants but no other known relatives with the condition

Case10: Female, 15 years report, Italy

HPOsFreeText: Height is 1.60 m, Weight is 59 kg, BMI is 23.0 kg/cm2, 8 years on ERT, Forced Vital Capacity at 106%

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

Case3: Male, 19 years report, Italy

CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

HPOsFreeText: Height is 1.78 m, Weight is 60 kg, BMI is 18.9 kg/cm2, 7 years on ERT, Forced Vital Capacity at 107%

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

Case11: Female, 16 years report, Italy

HPOsFreeText: Height is 1.62 m, Weight is 57 kg, BMI is 21.7 kg/cm2, 7 years on ERT, Forced Vital Capacity at 102%

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

Case4: Male, 17 years report, Italy

HPOsFreeText: Height is 1.88 m, Weight is 66 kg, BMI is 18.7 kg/cm2, 7 years on ERT, Forced Vital Capacity at 91%

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

Case6: Male, 21 years report, Italy

HPOsFreeText: Height is 1.74 m, Weight is 71 kg, BMI is 23.5 kg/cm2, 7 years on ERT, Forced Vital Capacity at 99%

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

Case1: Female, 46 years report, Italy

CasePresentingHPOs: HP:0003551 (Difficulty climbing stairs)

HPOsFreeText: Height is 1.64 m, Weight is 50 kg, BMI is 18.6 kg/cm2, 2 years on ERT, Forced Vital Capacity at 108%

CaseNotHPOs: HP:0002098 (Respiratory distress)

NotHPOsFreeText: Nocturnal non-invasive ventilation

CaseAddInfo: Late Onset Pompe Disease

CaseII: Adult onset, 71 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003326, HP:0003236, HP:0003198 (Proximal muscle weakness, Myalgia, Increased serum CK, Myopathy)

HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from dried blood spot: 0%, 6-Minute Walking Test: 40 min, Forced Vital Capacity Seated: 850 (22%)

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseIX: Early adult onset

CasePresentingHPOs: HP:0003701, HP:0003388, HP:0002795, HP:0001627 (Proximal muscle weakness, Easy fatiguability, Abnormal respiration, Abnormal heart morphology)

HPOsFreeText: Wheelchair-bound

CaseAddInfo: Late-Onset Pompe Disease

CaseV,1: Adolescent onset, 42 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388, HP:0003326 (Proximal muscle weakness, Increased serum CK, Easy fatigability, Myalgia)

HPOsFreeText: Plasma CK 5-10× Normal, Vacuoles in histology, 6-Minute Walking Test: 135 min, Forced Vital Capacity Seated: 950 (20%), GAA activity from dried blood spot: 0.20%

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseIV,1: Early adult onset, 40 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0002795, HP:0003546 (Proximal muscle weakness, Increased serum CK, Abnormal respiration, Exercise intolerance)

HPOsFreeText: Plasma CK 2.5–5× Normal, Vacuoles in histology

CaseAddInfo: Late-Onset Pompe Disease

CaseV,3: Child onset, 45 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236 (Proximal muscle weakness, Increased serum CK)

HPOsFreeText: Plasma CK 2.5-5× Normal, GAA activity from dried blood spot: 0.08%, 6-Minute Walking Test: 566 min

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseIII: Adult onset, 63 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198, HP:0002460, HP:0002015 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy, Distal muscle weakness, Dysphagia)

HPOsFreeText: Plasma CK 2.5–5× Normal, GAA activity from muscle: 11.7%

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseIV,4: Early adult onset, 45 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003546 (Proximal muscle weakness, Increased serum CK, Exercise intolerance)

HPOsFreeText: Plasma CK 2.5–5× Normal, Vacuoles in histology

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseI: Early adult onset, 49 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Easy fatigability, Increased serum CK, Myopathy)

HPOsFreeText: Plasma CK 5–10× Normal, GAA activity from lymphocytes: 14.2%

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseIV,3: Early adult onset, 50 years diagnosis

CasePresentingHPOs: HP:0003236, HP:0003546 (Increased serum CK, Exercise intolerance)

HPOsFreeText: Plasma CK 2.5–5× Normal

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseV,2: Adult onset, 33 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0003388 (Proximal muscle weakness, Increased serum CK, Easy fatigability)

HPOsFreeText: Plasma CK 5-10× Normal, 6-Minute Walking Test: 566 min, Forced Vital Capacity Seated: 3000 (90%), GAA activity from dried blood spot: 0.20%

CaseNotHPOs: HP:0002795 (Abnormal respiration)

CaseAddInfo: Late-Onset Pompe Disease

CaseIV,2: Early adult onset, 47 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0003236, HP:0002795, HP:0003546 (Proximal muscle weakness, Increased serum CK, Abnormal respiration, Exercise intolerance)

HPOsFreeText: Plasma CK 2.5–5× Normal

CaseAddInfo: Late-Onset Pompe Disease

Case9: Male, 40 years onset, 45 years diagnosis, 74 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

HPOsFreeText: Lost ambulation at 50 years, Started invasive ventilation at 67 years, Started ERT given every other week at a dose of 20 mg/kg at 70 years for 43 months, Peak Anti-rhGAA antibodies at 1:409,600, Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 29 to 26, 6MWT stayed constant at 0 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease

Case12: Male, 35 years onset, 50 years diagnosis, 61 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

HPOsFreeText: Lost ambulation at 48 years, Started invasive ventilation at 35 years, Started ERT given every other week at a dose of 20 mg/kg at 56 years for 49 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0 (L / % expected), MIP at 22 (cm H2O), MEP at 28 (cm H2O), Time off ventilation stayed constant at 0 min, 6MWT stayed constant at 0 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease

Case3: Male, 28 years onset, 30 years diagnosis, 69 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887, HP:0002093 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation, Respiratory insufficency)

HPOsFreeText: Lost ambulation at 58 years, Started invasive ventilation at 28 years, Started ERT given every other week at a dose of 20 mg/kg at 68 years for 11 months, Peak Anti-rhGAA antibodies at 1:1600, FVC at 0.45/13 (L / % expected), MIP at 17 (cm H2O), MEP at 29 (cm H2O), Time off ventilation stayed constant at 0, Total Motor Function Measure from 31 to 27

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease, Patient died before publication

Case1: Male, 62 years report

CasePresentingHPOs: HP:0002091, HP:0002878, HP:0003701, HP:0040047, HP:0002098, HP:0100786, HP:0006510, HP:0005978, HP:0000822, HP:0003124, HP:0001677, HP:0003236, HP:0004324, HP:0002329, HP:0030207, HP:0002098, HP:0040047, HP:0100750, HP:0002097, HP:0007269, HP:0040046 (Restrictive lung disease, Respiratory failure, Proximal muscle weakness, Abnormality of the right hemidiaphragm, Shortness of breath, Hypersomnia, Chronic obstructive pulmonary disease, Diabetes mellitus Type II, Hypertension, Hypercholesterolemia, Coronary artery disease, Elevated serum creatine kinase, Increased body weight, Drowsiness, Paradoxical respiration, Respiratory distress, Abnormality of the right hemidiaphragm, Atelectasis, Emphysema, Spinal muscular atrophy, Abnormality of the left hemidiaphragm)

HPOsFreeText: Hypercapnic respiratory failure, Chronic phrenic neuropathy bilaterally, Long history of apparently idiopathic right hemidiaphragm paralysis, Underwent muscle biopsy and electromyography, both of which showed nonspecific myopathic features associated with mild denervation, On presentation, the patient's vital signs were a temperature of 36.5 °C (97.7 °F); heart rate, 94 beats/minute; blood pressure, 104/70 mm Hg; respiratory rate, 22 breaths/minute; oxygen saturation, 90% when receiving 2 L of supplemental oxygen per minute; and body mass index, 29.9 kg/m2, Decreased air entry bilaterally, Laboratory values were: Hemoglobin, 120 g/L; platelets, 279 × 109/L; white blood cells, 7.7 × 109/L; sodium, 140 mmol/L; potassium, 5.1 mmol/L; bicarbonate, 40 mmol/L; serum urea nitrogen, 3.6 mmol/L; creatinine, 70.7 μmol/L; and calcium, 2.48 mmol/L, Fatty atrophy of rotator cuff musculature, Tests for resting room-air arterial blood gases showed a pH of 7.29; PCO2, 89.4 mm Hg; PO2, 67.6 mm Hg; and serum bicarbonate, 43 mmol/L, Right diaphragm paralysis, Electromyography showed complete absence of phrenic compound muscle action potentials bilaterally. No activation of motor unit potentials was seen within the diaphragm, either with respiration or with volitional effort. Ultrasonography showed that the left hemidiaphragm was hyperechoic, 0.14 cm thick at functional residual capacity (FRC), with a thickening ratio of 1.1 (the thickening ratio is thickness at total lung capacity/thickness at FRC). The right hemidiaphragm was hyperechoic, 0.15 cm thick at FRC, with thickening ratio of 0.9. (Normal thickness is >0.15 cm, normal thickening ratio is >1.2.) The aldolase concentration was slightly increased at 9 U/L (reference level, <7.7 U/L). To complete the evaluation for rarer causes of diaphragmatic dysfunction, neurology services requested testing for inherited neuropathies. Three weeks later, the patient's serum GAA level was 1.0 nmol/mL/hour (reference level, >7.4 nmol/mL/hour)

CaseNotHPOs: HP:0003549 (Abnormality of connective tissue)

NotHPOsFreeText: The following tests were within reference range: creatine kinase, thyroid function tests, erythrocyte sedimentation rate, serum and protein electrophoresis, antinuclear antibody profile, and anti-Jo antibodies

CaseAddInfo: Ex-Smoker with 40–80 pack-years of smoking, Medications at presentation to facility included aspirin, clopidogrel, simvastatin, diltiazem, sitagliptin, metformin, budesonide and formoterol inhaler, tiotropium bromide inhaler, and albuterol inhaler

Case1: Male, 21 years onset, 27 years diagnosis, 36 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case4a: Male, 46 years onset, 46 years diagnosis, 56 years report

CasePresentingHPOs: HP:0003236, HP:0002747 (Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease, Sibling of Patient 4

CaseA: Male, 10 months onset, 18 months diagnosis

CaseAPresentingHPOs: HP:0001270, HP:0003324 (Motor delay, Generalized weakness)

HPOsFreeText: CRIM positive

CaseNotHPOs: HP:0100543 (Cognitive impairment)

CaseAddInfo: Infantile-Onset Pompe Disease

Case4: Female, 25 years onset, 43 years diagnosis, 58 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease, Sibling of Patient 4a

Case8: Female, 18 years onset, 18.5 years diagnosis, 29 years report

CasePresentingHPOs: HP:0003325, HP:0003236 (Limb-girdle muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case14: Male, 28 years onset, 36 years diagnosis, 37 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0003691 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Scapula alata)

CaseAddInfo: Late-Onset Pompe Disease

Case10: Female, 47 years onset, 50 years diagnosis, 64 years report

CasePresentingHPOs: HP:0003325, HP:0003236 (Limb-girdle muscle weakness, Increased serum CK)

CaseAddInfo: Late-Onset Pompe Disease

Case12: Male, 15 years onset, 40 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Case15: Female, 13 years onset, 43 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Case20: Female, 3 years onset, 4 years diagnosis

CaseAddInfo: Late-Onset Pompe Disease

Case3: Male, 1 year report

CasePresentingHPOs: HP:0002910, HP:0002058 (Elevated liver enzymes, Myopathic facies)

HPOsFreeText: Nonspecific hyperCKemia, 847 CK (U/L), 0 GAA activity (µmol/L/h)

CaseNotHPOs: HP:0001627, HP:0002093 (Abnormality of the heart, Respiratory insufficiency)

Case2: Male, 2 years report

CasePresentingHPOs: HP:0002910, HP:0002058 (Elevated liver enzymes, Myopathic facies)

HPOsFreeText: Nonspecific hyperCKemia, 1710 CK (U/L), 0.1 GAA activity (µmol/L/h)

CaseNotHPOs: HP:0003457, HP:0001627, HP:0002093 (EMG abnormality, Abnormality of the heart, Respiratory insufficiency)

Case1: Female, 12 years report, 3 years onset, 12 years diagnosis

CasePresentingHPOs: HP:0003325, HP:0002093, HP:0002650 (Limb-girdle muscle weakness, Respiratory insufficiency, Scoliosis)

HPOsFreeText: 730 CK (U/L), Normal Heart, 0 GAA activity (µmol/L/h), Showed respiratory involvement and required nocturnal non-invasive ventilation, An ambulant patient with 284 m six minute walk distance at the time of diagnosis

CaseNotHPOs: HP:0003457, HP:0001627 (EMG abnormality, Abnormality of the heart)

NotHPOsFreeText: Muscle weakness confined to limb-girdle muscles

PatientF2P2: Female, 39 years diagnosis, Caucasian

CasePresentingHPOs: HP:0003323, HP:0003198, (Progressive muscle weakness, Myopathy)

HPOsFreeText: Had deficient muscle acid GAA activity (1.0 mmol/min/g, control >4.0 mmol/min/g)

CaseAddInfo: Mother of F2P1, the proband, who died at 8 months secondary to the disease.

Case4: 0.5 years diagnosis, Germany

CasePresentingHPOs: HP:0031185, HP:0001635, HP:0001252, HP:0001324, HP:0003236, HP:0001639 (Increased NT-proBNP level, Cardiac failure, Muscular hypotonia, Muscle weakness, Increased serum CK, Hypertrophic cardiomyopathy)

HPOsFreeText: 3924 BNP (pg/ml), 7.68 IVS (d) z score, 6.42 IVS (s) z score, Heart Failure at NYHA Class 3

NotHPOsFreeText: No left-ventricular outflow tract obstruction

CaseAddInfo: Infantile-Onset Pompe Disease

Case3HPOsFreeText: 5 mg/kg GAA treatment, GAA activity at 3.1 pmol/punch/hr, GAA activity at 31% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

Case1117: Male, 35 years onset, Welsh/English, Caucasian

CasePresentingHPOs: HP:0003560, HP:0005110 (Muscular dystrophy, Atrial fibrillation)

HPOsFreeText: 1,000 –2000's CK level, Immunohistochemistry: dystrophin, sarcoglycans, merosin

CaseNotHPOs: HP:0009051, HP:0002540 (Increased muscle glycogen content, Non-ambulatory)

Case3: Male, 35 years report, 5 years onset, Algeria, African

CasePresentingHPOs: HP:0003323, HP:0003749, HP:0002355, HP:0007340, HP:0008956, HP:0003484, HP:0003236, HP:0003198 (Progressive muscle weakness, Pelvic girdle muscle weakness, Difficulty walking, Lower limb muscle weakness, Proximal lower limb amyotrophy, Upper limb muscle weakness, Increased serum CK, Myopathy)

HPOsFreeText: At grade 3 of Vignos and Walton scales, CK rate was 5 times the normal value and AST and ALT were normal, EMG was compatible with a myopathic disorder, GAA activity measured in leukocytes was significantly decreased

CaseNotHPOs: HP:0003115, HP:0003116, HP:0001270, HP:0001290, HP:0002240, HP:0001640, HP:0005952, HP:0002540 (Abnormal ECG, Abnormal echocardiography, Motor delay, Generalized hypotonia, Hepatomegaly, Cardiomegaly, Decreased pulmonary function, Non-ambulatory)

Patient15: Male, 21 years report, 2 years onset

CasePresentingHPOs: N/A

HPOsFreeText: GAA activity 4.7% from a dried blood spot

CaseNotHPOs: HP:0002098, HP:0001324, HP:0001640, HP:0002240 (Respiratory distress, Muscle weakness, Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Case1: Male, French-Canadian, 18 years onset, 54 years diagnosis and report

CasePresentingHPOs: HP:0008994, HP:0000822, HP:0003119, HP:0004398, HP:0007185, HP:0009109, HP:0002094, HP:0012764, HP:0002098 (Proximal muscle weakness in lower limbs, High blood pressure, dyslipidemia, Peptic ulcer, Loss of consciousness, Denervation of the diaphragm, Dyspnea, Orthopnea, Shortness of breath)

HPOsFreeText: Dependent on continuous positive airway pressure or bilevel positive airway pressure when he is lying flat or sleeping because of previous intubation and tracheostomy, GAA activity measured from dried blood spot was 0.87 pmol/h/punch (Normal 4.96 - 27.3)

CaseAddInfo: Late Onset Pompe Disease, The patient’s mother had six miscarriages and died at age 75 of lung cancer and his father died of cardiac problems in his early sixties, It appears that no other family members, including his parents and two siblings, were affected, patient had a previous appendectomy, He has no allergies, stopped smoking in 2002, and denied any alcohol or drug use

Case9: No assertion made on age, gender or ethnicity

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: The identified variants were heterozygote in parents.

CasePresentingHPOs: HP:0005542

(Prolonged clotting time)

CaseHPOFreeText: Bleeding time greater than 20 minutes and hematocrit of 38.1%

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: N/A

CasePreviousTesting: Genetic study of patient was conducted using direct sequencing of entire coding and exon-intron boundaries of the ITGA2B and ITGB3 genes.

Gene: ITGA2B

Variant: NM_000419.3:c.1392A>G (p.Pro464Pro)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA500273575

gnomAD: https://gnomad.broadinstitute.org/variant/17-42458248-T-C

Case4: Patient RL

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs:

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: N/A

CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study

Gene: ITGA2B

Variant: NM_000419.3:c.1544+1G>A

LegacyVariant: N/A

ClinVar: 2895

CAiD: CA10575473

gnomAD: N/A

Case11: Patient Ssyl

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: N/A

CasePreviousTesting: The amplification of DNA fragments using PCR and their electrophoretic migration through a denaturing gradient was used to scan the entire coding region, splice site junctions and promoter regions of the GPIIb and GPIIIa genes for all 20 patients in this study

Gene: ITGB3

Variant: NM_000212.2:c.1955A>T (p.His652Leu)

LegacyVariant: (p.His626Leu)

ClinVar: N/A

CAiD: CA400032927

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case20: GT23, Male, 19, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978, HP:0000225, HP:0000421

(Easy bruising, gingival bleeding, epistaxis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)

PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGB3

Variant: NM_000212.2:c.1031A>C (p.Tyr344Ser)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400025814

gnomAD: N/A

Supplementary Table S1 & S2 Proband and Variant Information:

Case6: GT7, Female, 19, French

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: 1 brother, that is all the information Supp table S1 gives us

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000978 and HP:0000421

(Easy bruising and epistaxis)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed <10-15% expression of αIIbβ3 (See Supplementary Table 1)

PlateletAggregation: Absent ADP but some response with other agonists (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGB3

Variant: NM_000212.2:c.187C>T (p.Arg63Cys) and NM_000212.2:c.505C>T (p.Arg169Ter)

LegacyVariant: N/A

ClinVar: 631774

CAiD: CA8622892 and CA291224658

gnomAD: MAF in the East Asian population is 0.00005012 http://gnomad.broadinstitute.org/variant/17-45360741-C-T

Supplementary Table S1 & S2 Proband and Variant Information:

Case9: GT10, Male, 45, French and Italian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Mild lifelong bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed 30-50% variant expression of αIIbβ3 (See Supplementary Table 1)

PlateletAggregation: Residual platelet aggregation (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGA2B

Variant: NM_000419.3:c.1440-13_1440-1del (p.Arg480Serfs*106) and NM_000419.3:c.3077G>A (p.Arg1026Gln)

LegacyVariant: N/A

ClinVar: 50232

CAiD: CA913184940 and CA10575572

gnomAD: MAF in the European (non-Finnish) population 0.00006482 http://gnomad.broadinstitute.org/variant/17-45363676-T-C and MAF in the European (non-Finnish) population is 0.000008801 http://gnomad.broadinstitute.org/variant/17-42449775-C-T

Supplementary Table S1 & S2 Proband and Variant Information:

Case10: GT11, Female, 54, French and German

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132

(Epistaxis, gingival bleeding, menorrhagia)

CaseHPOFreeText: Spontaneous bruising

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed 10-15% variant expression of αIIbβ3 (See Supplementary Table 1)

PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGA2B

Variant: NM_000419.3:c.1073G>A (p.Arg358His) and NM_000419.3:c.1234G>A (p.Gly412Arg)

LegacyVariant: N/A

ClinVar: 2896 and 381748

CAiD: CA115839 and CA8603182

gnomAD: MAF in the Latino population is 0.0001453 http://gnomad.broadinstitute.org/variant/17-42458406-C-T

Supplementary Table S1 & S2 Proband and Variant Information:

Case54: GT54, Male, 33, Argintinian/Italian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225, HP:0006298

(Gingival bleeding, bleeding following tooth extraction)

CaseHPOFreeText: Hematomas

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: Flow cytometry showed <5% expression of αIIbβ3 (See Supplementary Table 1)

PlateletAggregation: Absent platelet aggregation (See Supplementary Table 1)

CasePreviousTesting: Sanger sequencing of ITGA2B and ITGB3

Gene: ITGB3

Variant: NM_000212.2:c.2014+1G>A and a "LR deletion variant" as mentioned in Sup Table 1

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400033055

gnomAD: N/A

Case1: (Proband CabGT-1) Male, age not specified, China

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

ProteinExpression: Surface expression detected by flow cytometry showed <5% GPIIb and <5% GPIIIa

Platelet Aggregation: N/A

CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

Gene: ITGA2B

Variant: NM_000419.3:c.531T>A (p.Cys177Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290955739

gnomAD N/A

Case7: (Proband CabGT-7) Female, age not specified, Caucasian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

ProteinExpression: Flow cytometry showed <5% GPIIb and 11% GPIIIa surface expression

Platelet Aggregation: N/A

CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

Gene: ITGA2B

Variant: The first variant was found to be: NM_000419.3:c.1563T>A (p.Cys521Ter) and they did not find the second mutation

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290950094

gnomAD N/A

Case3: (Proband CabGT-3), Male, age not specified, European Caucasian

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

ProteinExpression: N/A

Platelet Aggregation: N/A

CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

Gene: ITGA2B

Variant: NM_000419.3:c.1214T>C (p.Ile405Thr) and c.1442-13_1442-1del, which is not showing up in CAR (Unregistered Variant?)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290950815 (p.Ile405Thr)

gnomAD N/A

Case9: (Proband CabGT-9), Female, age not specified, Kuwait

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

ProteinExpression: N/A

Platelet Aggregation: N/A

CasePreviousTesting: Promoter and exon sequences of aIIb and b3 genes were amplified and directly sequence

Gene: ITGA2B

Variant: NM_000419.3:c.1879-2A>G

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA290949031

gnomAD N/A

Supplementary Table S1:

Case41: GT48, French, gender and age not specified here at this time

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGB3

Variant: NM_000212.2:c.1094A>G (p.Asn365Ser) and NM_000212.2:c.1522del (p.Gln508SerfsTer161)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400026292 and CA772541579

gnomAD: N/A

Supplementary Table S1:

Case23: GT26, French, gender and age not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGA2B

Variant: NM_000419.3:c.1073G>A (p.Arg358His)

LegacyVariant: N/A

ClinVar: 2896

CAiD: CA115839

gnomAD: N/A

Supplementary Table S1:

Case10: GT11, French/German, age and gender not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGA2B

Variant: NM_000419.3:c.1073G>A (p.Arg385His) NM_000419.3:c.1234G>A (p.Gly412Arg)

LegacyVariant: N/A

ClinVar: 2896 and 381748

CAiD: CA115839 and CA8603182

gnomAD: MAF in the Latino population for (p.Gly412Arg) is 0.0001453 https://gnomad.broadinstitute.org/variant/17-42458406-C-T

Supplementary Table S1:

Case65: GT76, French, gender and age are not specified

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: All patients had a life-long history of mucocutaneous bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: All patients in this study met the clinical and platelet function requirements for GT-- this includes an absent or strongly reduced expression of alphaIIbBeta3 in platelets

PlateletAggregation: All patients in this study met the clinical and platelet function requirements for GT-- this includes absent or severely reduced platelet aggregation with at least three physiological agonists

CasePreviousTesting: Sanger sequencing was performed. Sanger sequencing ensured coverage of all exons and splice sties of the ITGA2B and ITGB3 genes and extended 300-500 bp into the introns as well as including the UTR. They sequenced 416 bp upstream of the ITGA2B promoter and 463 bp upstream of the ITGB3 promoter. In total they sequenced 51.2% of the ITGA2B gene and 19.4% of the larger ITGB3 gene

Gene: ITGA2B

Variant: NM_000419.3:c.2421G>A (p.Trp807Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399796017

gnomAD: N/A

Case1: Patient F1P1, Male, 11 years old, Tunisian

DiseaseAssertion: Glanzmann thrombasthenia type I

FamilyInfo: Table 1 states there is a family history of bleeding (we have minimal to no specific info on this)

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000225, HP:0000978

(Gingival bleeding, easy bruising)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: GT diagnosis was based on absent platelet aggregation induced by ADP, collagen, and TRAP and subnormal or cyclical ristocetin induced agglutination

CasePreviousTesting: Using PCR they successfully amplified 20 DNA fragments for the ITGA2B gene (covering more than 48% of the ITGA2B gene constituting 30 exons) and15 DNA fragments of theITGB3gene (covering 15 exons)

Gene: ITGB3

Variant: NM_000212.2:c.176T>C (p.Leu59Pro) and NM_000212.2:c.1143A>C (p.Val381Val) and NM_000212.2:c.1545G>A (p.Arg515Arg) and the other variant stated here is g.41037G>C which I am marking as an Unknown Variant-- biocurator should look at this and determine variant

LegacyVariant: N/A

ClinVar: 13558 (p.Leu59Pro), 255535 (p.Val381Val), 255537 (p.Arg515Arg)

CAiD: CA123235 (p.Leu59Pro), CA8623175 (p.Val381Val), CA8623284 (p.Arg515Arg)

gnomAD: MAF in the Ashkenazi Jewish population is 0.1565 https://gnomad.broadinstitute.org/variant/17-45360730-T-C for (p.Leu59Pro) and MAF in the East Asian population is 0.5857 https://gnomad.broadinstitute.org/variant/17-45368337-A-C for (p.Val381Val) and MAF in the East Asian population for (p.Arg515Arg) is 0.3455 https://gnomad.broadinstitute.org/variant/17-45369789-G-A

Case6: Female, Iraq, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0000132, HP:0031364

(Epistaxis, gingival bleeding, menorrhagia, ecchymosis)

CaseHPOFreeText: Post-partum bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGB3

Variant: NM_000212.2:c.2031_2041del (p.Asp677Glufs)

LegacyVariant: (p.Asp651Glufs*3)

ClinVar: N/A

CAiD: CA915940605

gnomAD: N/A

Case13: Female, Iraq, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0031364, HP:0000132, HP:0002239, HP:0002573

(Epistaxis, gingival bleeding, ecchymosis, menorrhagia, gastrointestinal bleeding, rectal bleeding)

CaseHPOFreeText: Haemarthrosis, DIC

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGB3

Variant: NM_000212.2:c.2031_2041del (p.Asp677Glufs)

LegacyVariant: (p.Asp651Glufs*3)

ClinVar: N/A

CAiD: CA915940605

gnomAD: N/A

Case14: Female, Arab, age not specified

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: Table 1 mentions family history available for the proband, however no specific details about family provided in paper

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0000225, HP:0031364, HP:0000132

(Epistaxis, gingival bleeding, ecchymosis, menorrhagia)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: N/A

CasePreviousTesting: N/A

Gene: ITGA2B

Variant: NM_000419.3:c.409-2_419del

LegacyVariant: N/A

ClinVar: 2889

CAiD: CA10575471

gnomAD: N/A

Case2: Male, 10 years old, Andra Pradesh India

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0000421, HP:0031364, HP:0002239, HP:0000225

(Epistaxis, ecchymosis, GI bleeding, gingival bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 1 for values

PlateletAggregation: See Table 1 for values

CasePreviousTesting: PCR amplification of ITAG2B and ITGB3

Gene: ITGA2B

Variant: NM_000419.3:c.475G>A (p.Gly159Ser)

LegacyVariant: (p.Gly128Ser)

ClinVar: N/A

CAiD: CA8603454

gnomAD: MAF in the South Asian population is 0.00003267 https://gnomad.broadinstitute.org/variant/17-42463018-C-T

Case1: Male, 13 years old, Andra Pradesh India

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: HP:0006298, HP:0000421, HP:0000967, HP:0002239, HP:0000225

(Prolonged bleeding after dental extraction, epistaxis, petechiae, GI bleeding, gingival bleeding)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: See Table 1 for values

PlateletAggregation: See Table 1 for values

CasePreviousTesting: PCR amplification of ITAG2B and ITGB3

Gene: ITGA2B

Variant: NM_000419.3:c.48G>A (p.Trp16Ter)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA399807046

gnomAD: N/A

Case4: No gender, age, or ethnicity provided. Patient followed in Germany

DiseaseAssertion: Glanzmann thrombasthenia

FamilyInfo: N/A

ParentalGenotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Severe bleeding

CaseNotHPOs: N/A

CaseNotHPOsFreeText: N/A

ProteinExpression: N/A

PlateletAggregation: Minimal information, not specific enough

CasePreviousTesting: Sanger sequencing identified disease-causing variants in 18 out of 20 patients (Probands 6 and 14 excluded) with istoantibodies to αIIbβ3. The mutations were evenly distributed between ITGB3 and ITGA2B.

Gene: ITGB3

Variant: NM_000212.2:c.1717T>C (p.Cys573Arg)

LegacyVariant: N/A

ClinVar: N/A

CAiD: CA400032387

gnomAD: N/A