A novel biallelic loss-of-function variant in DAND5 causes heterotaxy syndrome

Mythily Ganapathi, Christie M. Buchovecky, Fernando Cristo, Priyanka Ahimaz, Carrie Ruzal-Shapiro, Karen Wou, José M. Inácio, Alejandro Iglesias, José A. Belo, Vaidehi Jobanputra

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Abstract

The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in DAND5, a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a DAND5 biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrelated individual with heterotaxy syndrome and a homozygous frameshift variant in DAND5 (NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that the DAND5 c.197del variant is unable to inhibit nodal signaling when compared with the wild-type expression construct. This work strengthens the genetic and functional evidence for biallelic LoF variants in DAND5 causing an autosomal recessive heterotaxy syndrome.

Original languageEnglish
JournalCold Spring Harbor molecular case studies
Volume8
Issue number7
DOIs
Publication statusPublished - 1 Dec 2022

Keywords

  • abdominal situs inversus

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