Premium
Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome
Author(s) -
Zhang Chaofan,
Mazzeu Juliana F.,
Eisfeldt Jesper,
Grochowski Christopher M.,
White Janson,
Akdemir Zeynep C.,
Jhangiani Shalini N.,
Muzny Donna M.,
Gibbs Richard A.,
Lindstrand Anna,
Lupski James R.,
Sutton V. Reid,
Carvalho Claudia M. B.
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61908
Subject(s) - genetics , sanger sequencing , biology , wnt signaling pathway , locus (genetics) , exome sequencing , gene , exome , allele , hnf1a , dna sequencing , mutation
Robinow syndrome (RS) is a genetically heterogeneous disorder characterized by skeletal dysplasia and a distinctive facial appearance. Previous studies have revealed locus heterogeneity with rare variants in DVL1 , DVL3 , FZD2 , NXN , ROR2 , and WNT5A underlying the etiology of RS. The aforementioned “Robinow‐associated genes” and their gene products all play a role in the WNT/planar cell polarity signaling pathway. We performed gene‐targeted Sanger sequencing, exome sequencing, genome sequencing, and array comparative genomic hybridization on four subjects with a clinical diagnosis of RS who had not had prior DNA testing. Individuals in our cohort were found to carry pathogenic or likely pathogenic variants in three RS related genes: DVL1 , ROR2 , and NXN . One subject was found to have a nonsense variant (c.817C > T [p.Gln273*]) in NXN in trans with an ~1 Mb telomeric deletion on chromosome 17p containing NXN , which supports our contention that biallelic NXN variant alleles are responsible for a novel autosomal recessive RS locus. These findings provide increased understanding of the role of WNT signaling in skeletal development and maintenance. These data further support the hypothesis that dysregulation of the noncanonical WNT pathway in humans gives rise to RS.