A Novel Biallelic Loss-of-Function Variant in DAND5 Causes Heterotaxy Syndrome.

The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in over fifty genes are known to causeheterotaxy. 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, Bolkier et al 2021, reported the first case of 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 to 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.