A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A

Scientific Reports
Till Joscha DemalSalim Abdelilah-Seyfried

Abstract

The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein's anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aap.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.

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Citations

May 15, 2020·Italian Journal of Pediatrics·Flaminia PugnaloniPaolo Versacci
Dec 10, 2020·Current Developments in Nutrition·Radha O JoshiPrachi Kukshal
Jun 23, 2021·Journal of the American Heart Association·Jordan E MorningstarRussell A Norris

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Datasets Mentioned

BETA
BC115245.1

Methods Mentioned

BETA
exome sequencing
Fluorescence
antisense oligonucleotide
transgenic
Fluorescence microscopy
in vitro transcription
scanning electron microscopy

Software Mentioned

MERLIN
SIFT
Ensembl
Adobe
MutationTaster2
Complete Genomics
PolyPhen2
Fiji
Adobe Illustrator
CADD

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