Odelia Chorin, Yoav Bolkier, Uriel Katz, Yishay Salem, Yair Anikster, Nechama Shalva, Ortal Barel, Moshe Giladi, Rotem Semo-Oz, Dror Ben-Ruby, Shelly Lev-Hochberg, Hadas Ityel, Lior Greenbaum, Asaf Vivante, Annick Rein-Rothschild, Ben Pode-Shakked
DAND5 has recently been suggested as a candidate gene in heterotaxy and CHDs. Our findings further support biallelic loss of function variants in DAND5 autosomal recessive laterality defects.
BACKGROUND: Laterality defects are rare congenital malformations that encompass congenital heart defects (CHDs) together with abnormalities of visceral organ arrangement (situs inversus or situs ambiguous). These defects may be isolated or part of a syndromic presentation with multisystem involvement. While over 50 genes have been implicated in laterality disorders, across multiple modes of inheritance, many cases remain molecularly undiagnosed. We sought to elucidate the molecular basis of dextrocardia, CHDs and visceral heterotaxy in two unrelated individuals of Arab-Muslim descent.
METHODS: Detailed clinical phenotyping and exome sequencing (ES) were performed for each of the probands, followed by familial segregation analysis.
RESULTS: ES revealed a shared homozygous variant in the Dan Domain Family Member 5 (DAND5) gene (NM_152654.3): c.396_397dup, p.(Tyr133SerfsTer11). DAND5 encodes a member of the Cerberus-related DAN protein family, which is involved in the establishment of left body asymmetry. This frameshift variant introduces a premature stop codon within the final exon, which is predicted to escape nonsense-mediated decay (NMD), resulting in a truncated protein lacking the functional DAN domain.
CONCLUSIONS: DAND5 has recently been suggested as a candidate gene in heterotaxy and CHDs. Our findings further support biallelic loss of function variants in DAND5 autosomal recessive laterality defects.