Dilated-Left Ventricular Non-Compaction Cardiomyopathy in a Pediatric Case with SPEG Compound Heterozygous Variants

International audienc

Identification of non-synonymous variations in ROBO1 and GATA5 genes in a family with bicuspid aortic valve disease

International audienc

Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome

BACKGROUND: Genetic cardiac diseases are the main trigger of sudden cardiac death (SCD) in young adults. Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiomyopathy and accounts for 0.5 to 1% of SCD cases per year. METHODS: Herein, we report a family with a marked history of SCD focusing on one SCD young adult case and one pediatric case with HCM. RESULTS: For the deceased young adult, postmortem whole‐exome sequencing (WES) revealed a missense variant in the ACTN2 gene: c.355G > A; p.(Ala119Thr) confirming the mixed hypertrophic/dilated cardiomyopathy phenotype detected in the autopsy. For the pediatric case, WES allowed us the identification of a novel frameshift variant in the LZTR1 gene: c.1745delT; p.(Val582Glyfs*10) which confirms a clinical suspicion of HCM related to Noonan syndrome. CONCLUSION: The present study adds further evidence on the pathogenicity of ACTN2: p. Ala119Thr variant in SCD and expands the mutational spectrum of the LZTR1 gene related to Noonan syndrome

Variations in the poly-histidine repeat motif of HOXA1 predispose individuals to bicuspid aortic valve

Abstract Bicuspid aortic valve (BAV) is the most common cardiovascular malformation (0.5–1.2% of the population) and is often associated with premature aortic valve stenosis or insufficiency, aortic aneurysm and other congenital cardiac heart defects. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the association of novel variants in the transcription factor HOXA1 with BAV in humans. Targeted sequencing of HOXA1 in a cohort of 333 BAV patients identified rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis revealed that disruption of the histidine repeat motif causes a significant reduction in the half-life of the protein, and that these variants are associated with a defective transcriptional activity of the HOXA1 protein. Targeting the zebrafish hoxa1a ortholog in vivo resulted in aortic valve defects that could be rescued by expressing the wild-type human HOXA1 . Furthermore, expression of HOXA1 Histidine variants in zebrafish also impacted aortic valve development indicating a dominant negative effect of these mutated proteins. Lastly, homozygous knockout mice for Hoxa1 develop a BAV phenotype, which is associated with a very small, rudimentary non-coronary leaflet. Genetic lineage analysis indicates that this defect is caused by a strong reduction of mesenchymal cells in the intercalated cushion due to a failure of neural crest cell migration toward the heart which is consistent with our transcriptomic analysis showing a down-regulation of premigratory and migratory neural crest markers in Hoxa1 −/− compared with control embryos. Together, these findings indicate that variants causing HOXA1 dysfunction play a significant role in the genetic cause of BAV in humans