Genetic architecture and phenotypic landscape of deafness and onychodystrophy syndromes

Abstract

Deafness and onychodystrophy syndromes are a group of phenotypically overlapping syndromes, which include DDOD syndrome (dominant deafness-onychodystrophy), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and Zimmermann-Laband syndrome (gingival hypertrophy, coarse facial features, hypoplasia or aplasia of nails and terminal phalanges, intellectual disability, and hypertrichosis). Pathogenic variants in four genes, ATP6V1B2, TBC1D24, KCNH1 and KCNN3, have been shown to be associated with deafness and onychodystrophy syndromes. ATP6V1B2 encodes a component of the vacuolar H⁺-ATPase (V-ATPase) and TBC1D24 belongs to GTPase-activating protein, which are all involved in the regulation of membrane trafficking. The overlapping clinical phenotype of TBC1D24- and ATP6V1B2- related diseases and their function with GTPases or ATPases activity indicate that they may have some physiological link. Variants in genes encoding potassium channels KCNH1 or KCNN3, underlying human Zimmermann-Laband syndrome, have only recently been recognized. Although further analysis will be needed, these findings will help to elucidate an understanding of the pathogenesis of these disorders better and will aid in the development of potential therapeutic approaches. In this review, we summarize the latest developments of clinical features and molecular basis that have been reported to be associated with deafness and onychodystrophy disorders and highlight the challenges that may arise in the differential diagnosis.