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A novel biallelic loss-of-function variant in DAND5 causes 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 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.

SUBMITTER: Ganapathi M 

PROVIDER: S-EPMC9808554 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A novel biallelic loss-of-function variant in <i>DAND5</i> causes heterotaxy syndrome.

Ganapathi Mythily M   Buchovecky Christie M CM   Cristo Fernando F   Ahimaz Priyanka P   Ruzal-Shapiro Carrie C   Wou Karen K   Inácio José M JM   Iglesias Alejandro A   Belo José A JA   Jobanputra Vaidehi V  

Cold Spring Harbor molecular case studies 20221228 7

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 <i>DAND5</i>, 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 <i>DAND5</i> biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrela  ...[more]

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