Author(s): Ganapathi, Mythily ; Buchovecky, Christie M. ; Cristo, Fernando ; Ahimaz, Priyanka ; Ruzal-Shapiro, Carrie ; Wou, Karen ; Inácio, José M. ; Iglesias, Alejandro ; Belo, José A. ; Jobanputra, Vaidehi
Date: 2022
Persistent ID: http://hdl.handle.net/10362/147243
Origin: Repositório Institucional da UNL
Subject(s): abdominal situs inversus; Medicine(all)
Funding J.A.B. acknowledges funding from iNOVA4Health-UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência through national funds and cofunded by Fundo Europeu de Desenvolvimento Regional (FEDER) under the PT2020 Partnership Agreement.
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.
