A novel biallelic loss-of-function variant inDAND5causes heterotaxy syndrome

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 inDAND5, 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 aDAND5biallelic 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 inDAND5(NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that theDAND5c.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 inDAND5causing an autosomal recessive heterotaxy syndrome.