New Variant With a Previously Unrecognized Mechanism of Pathogenicity in Hypertrophic Cardiomyopathy

Aguib, Yasmine; Allouba, Mona; Walsh, Roddy; Ibrahim, Ayman; Halawa, Sarah; Afify, Alaa M; Hosny, Mohamed; Theotokis, Pantazis; Galal, Aya; Elshorbagy, Sara; Roshdy, Mohamed; Kassem, Heba Sh.; Ellithy, Amany; Buchan, Rachel; Whiffin, Nicola; Anwer, Shehab; Cook, Stuart A.; Moustafa, Ahmed; ElGuindy, Ahmed; Ware, James S.; Barton, Paul J.R.; Yacoub, Magdi H.

doi:10.1161/circulationaha.120.048295

Cited by 5 publications

(7 citation statements)

References 5 publications

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“…MYH7 was the clear exception to this pattern, where increased risk of HF was limited to damaging missense carriers; pLoF carrier status conferred no additional risk of HF. This supports previous observations that missense variants in MYH7 tend to cause HCM through gain-of-function mechanisms, and highlights the comparatively limited evidence supporting a direct relationship between most loss-of-function truncating variants in MYH7 and cardiomyopathy [31][32][33] .…”

Section: Rare-variant Associations In Mendelian Cardiomyopathy Genessupporting

confidence: 90%

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum

Lee,

Cardone,

Zhang

et al. 2023

Preprint

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Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, linking rare genetic variants to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multi-ancestry populations including 207,346 individuals from HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5x10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies in the Penn Medicine BioBank uncover exome-wide significant (p < 3.03x10-6) associations for HF and rare predicted loss-of-function variants in TTN and MYBPC3. Although the total burden heritability of rare coding variants in HF (3.5%, 95% CI 0.94-6.0%) is comparable to common variant heritability (4.3%, 95% CI 3.9-4.7%), burden heritability is highly concentrated in a small set of Mendelian cardiomyopathy genes (30.4% explained by TTN, LMNA, FLNC, and MYBPC3), while common-variant heritability is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

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Section: Rare-variant Associations In Mendelian Cardiomyopathy Genessupporting

confidence: 90%

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum

Lee,

Cardone,

Zhang

et al. 2023

Preprint

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“…However, some key differences are observed between the Egypt HCM and UK HCM cohorts. For example, we have recently reported the identification of a new class of pathogenic variants in HCM; a nonsense mediated decay-incompetent frameshift variant (c.5769delG) in MYH7 , which was recurrently observed in Egyptian patients (3.3%) and absent from large-scale (n>6,000) HCM patients of predominantly European ancestry 16,18 . Also, the Egypt HCM data shows an enrichment of JPH2 missense variants (5.2% Egypt HCM vs. 1.4% UK HCM genotype-positive patients) which rarely cause HCM outside of founder populations.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, MYH7 truncating variants accounted for a higher proportion of genotype-positive patients in the Egypt HCM cohort, which is explained by the recurrent variant c.5769delG [p.Ser1924AlafsTer9]. This variant was present in 3.3% of Egypt HCM patients and we recently showed that it causes HCM by introducing a distal premature termination codon, which escapes nonsense mediated decay resulting in the expression of an abnormal protein 16 . Several recurrent truncating variants in MYBPC3 were also detected, with two of these (c.1516delG [p.Asp506ThrfsTer7] (0.97%, n=5) and c.534_541delGGCCGGCG [p.Ala179GlnfsTer59] (1.36%, n=7)) likely to be Egyptian/North African specific founder variants.…”

Section: Differences In the Genetic Architecture Of Hcm Between Egypt...mentioning

confidence: 93%

“…Therefore, extending genomic research to diverse ancestral populations will not only reduce health disparities as we move towards precision-based HCM patient management but may also enhance variant interpretation for diagnosis, and provide novel genetic and mechanistic insights into the disease. For example, we have recently reported the identification of a new class of HCM pathogenic variants in MYH7, which was enriched in Egyptian patients over ancestry-matched controls and absent from large-scale HCM patients of predominantly European ancestry [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

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Influence of ethnicity and consanguinity on the genetic architecture of Hypertrophic Cardiomyopathy: insights from an understudied population

Allouba

Walsh

Afify

et al. 2022

Preprint

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Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition characterized by phenotypic heterogeneity that could partly be explained by the variability in genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. Here, we leverage ancestry-matched Egyptian patients (n=514) and deeply-phenotyped controls (n=400) to accurately define the genetic architecture of HCM. We also compare HCM variation between Egyptian and predominantly European patients to identify genetic features unique to consanguineous populations in Middle East and North Africa (MENA), which are likely to represent important contributors to disease. We report a higher prevalence of homozygous variants in Egyptian patients (4.1% vs 0.1%, p-value=2x10-7), with variants in the minor HCM genes MYL2, MYL3 and CSRP3 more likely to present in homozygosity than the major genes (MYH7, MYBPC3), suggesting that these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (5-fold greater than European patients), highlighting the importance of recessive inheritance/genes in consanguineous populations. Finally, significantly fewer rare variants detected in Egyptian HCM patients could be classified as (likely) pathogenic compared to Europeans (40.8% vs. 61.6%, p-value=1.6x10-5) due to the underrepresentation of MENA populations in current HCM databases. This proportion increased to 53.8% after incorporating methods that compare variant frequencies between Egyptian patients and controls. Together, our findings demonstrate that studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.

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“…For example, we have recently reported the identification of a new class of HCM pathogenic variants in MYH7 , which was enriched in Egyptian patients over ancestry-matched controls and absent from large-scale HCM patients of majority European ancestry. 16–18 …”

Section: Introductionmentioning

confidence: 99%

Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy

Allouba

Walsh

Afify

et al. 2023

European Heart Journal

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Aims Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity that is partly explained by the diversity of genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. The aim is to define the genetic architecture of HCM in North African cohorts with high consanguinity using ancestry-matched cases and controls. Methods and results Prospective Egyptian patients (n = 514) and controls (n = 400) underwent clinical phenotyping and genetic testing. Rare variants in 13 validated HCM genes were classified according to standard clinical guidelines and compared with a prospective HCM cohort of majority European ancestry (n = 684). A higher prevalence of homozygous variants was observed in Egyptian patients (4.1% vs. 0.1%, P = 2 × 10−7), with variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (five-fold greater than European patients), highlighting the importance of recessive inheritance in consanguineous populations. Finally, rare variants in Egyptian HCM patients were less likely to be classified as (likely) pathogenic compared with Europeans (40.8% vs. 61.6%, P = 1.6 × 10−5) due to the underrepresentation of Middle Eastern populations in current reference resources. This proportion increased to 53.3% after incorporating methods that leverage new ancestry-matched controls presented here. Conclusion Studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.

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New Variant With a Previously Unrecognized Mechanism of Pathogenicity in Hypertrophic Cardiomyopathy

Cited by 5 publications

References 5 publications

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum

Common- and rare-variant genetic architecture of heart failure across the allele frequency spectrum

Influence of ethnicity and consanguinity on the genetic architecture of Hypertrophic Cardiomyopathy: insights from an understudied population

Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy

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