Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.

TitleNovel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome.
Publication TypeJournal Article
Year of Publication2020
AuthorsZhang, C, Mazzeu, JF, Eisfeldt, J, Grochowski, CM, White, J, Akdemir, ZC, Jhangiani, SN, Muzny, DM, Gibbs, RA, Lindstrand, A, Lupski, JR, V Sutton, R, Carvalho, CMB
JournalAm J Med Genet A
Date Published2020 Oct 13

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.

Alternate JournalAm J Med Genet A
PubMed ID33048444
Grant ListUM1HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R03 HD092569 / HD / NICHD NIH HHS / United States
R03HD092569 / / Eunice Kennedy Shriver National Institute of Child Health and Human Development /
2017-02936 / / Swedish Research Council /