Mutation in mitral valve prolapse susceptible gene DCHS1 causes familial mitral annular disjunction.
J Med Genet
; 61(2): 125-131, 2024 Jan 19.
Article
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| MEDLINE
| ID: mdl-37399314
ABSTRACT
BACKGROUND:
Mitral annular disjunction (MAD) is an under-recognised phenotype associated with severe ventricular arrhythmias. Limited knowledge has been gained on its molecular genesis.METHODS:
A total of 150 unrelated deceased Chinese were collected for whole-exome sequencing, with analysis focusing on a panel of 118 genes associated with 'abnormal mitral valve morphology'. Cases were prespecified as 'longitudinally extensive MAD (LE-MAD)' or 'longitudinally less-extensive MAD (LLE-MAD)' according to the gross disjunctional length with a cut-off of 4.0 mm. The pedigree investigation was conducted on a case carrying an ultra-rare (minor allele frequency <0.1%) deleterious variant in DCHS1.RESULTS:
Seventy-seven ultra-rare deleterious variants were finally identified. Exclusively, 12 ultra-rare deleterious variants distributed in nine genes occurred in LE-MAD, which were ANK1, COL3A1, DCHS1, FBN2, GNPTAB, LZTR1, PLD1, RYR1 and VPS13B. Ultra-rare deleterious variants in those nine genes were predominantly distributed in LE-MAD compared with LLE-MAD (28% vs 5%, OR 7.30, 95% CI 2.33 to 23.38; p<0.001), and the only gene related to LE-MAD with borderline significance was DCHS1. LE-MAD was consistently observed in a sizeable Chinese family, in which LE-MAD independently co-segregated with an ultra-rare deleterious variant in DCHS1, rs145429962.CONCLUSION:
This study initially proposed that isolated LE-MAD might be a particular phenotype of MAD with a complex genetic predisposition. Deleterious variants in DCHS1 might be associated with the morphogenesis of LE-MAD.Palabras clave
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Prolapso de la Válvula Mitral
/
Enfermedades de las Válvulas Cardíacas
Tipo de estudio:
Etiology_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Genet
Año:
2024
Tipo del documento:
Article
País de afiliación:
China