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 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.

Automated summary

The majority of heterotaxy cases do not have a molecular diagnosis, but it is known that pathogenic variants in more than 50 genes can cause this condition. In this study, two unrelated individuals with heterotaxy syndrome were found to have biallelic loss-of-function variants in the DAND5 gene. Experimental results showed that these variants resulted in the inability of DAND5 to inhibit nodal signaling. This study reinforces the genetic and functional evidence for the role of DAND5 gene in causing heterotaxy syndrome.