A novel biallelic loss-of-function variant in DAND5 causes heterotaxy syndrome
- Mythily Ganapathi1,5,
- Christie M. Buchovecky1,5,
- Fernando Cristo2,
- Priyanka Ahimaz3,
- Carrie Ruzal-Shapiro4,
- Karen Wou3,
- José M. Inácio2,
- Alejandro Iglesias3,
- José A. Belo2 and
- Vaidehi Jobanputra1
- 1Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York 10032, USA;
- 2Stem Cells and Development Laboratory, iNOVA4Health, NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1099-085 Lisboa, Portugal;
- 3Department of Pediatrics, Columbia University Irving Medical Center, New York, New York 10032, USA;
- 4Department of Radiology, Columbia University Irving Medical Center, New York, New York 10032, USA
- Corresponding author: vj2004{at}cumc.columbia.edu
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↵5 These authors contributed equally to this work.
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.
Footnotes
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[Supplemental material is available for this article.]
- Received September 16, 2022.
- Accepted October 25, 2022.
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