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

• Published in: American journal of medical genetics. Part A Vol. 185; no. 12; pp. 3593 - 3600
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2021; Wiley Subscription Services, Inc
• Subjects: Bone dysplasia; Chromosome 17; Chromosome deletion; Chromosomes, Human, Pair 17 - genetics; clinical diagnosis; Comparative Genomic Hybridization; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - physiopathology; deletion; Dishevelled protein; Dishevelled Proteins - genetics; Dwarfism - genetics; Dwarfism - physiopathology; Dysplasia; Etiology; Female; Genes; Genes, Dominant - genetics; Genes, Recessive - genetics; Genetic Heterogeneity; Genetic Predisposition to Disease; Genomic Structural Variation - genetics; Genomics; Humans; Hybridization; Limb Deformities, Congenital - genetics; Limb Deformities, Congenital - physiopathology; Male; missense; Oxidoreductases - genetics; Polarity; Receptor Tyrosine Kinase-like Orphan Receptors - genetics; Signal transduction; skeletal dysplasia; Skeleton; structural variant; Urogenital Abnormalities - genetics; Urogenital Abnormalities - physiopathology; Whole Exome Sequencing; Whole Genome Sequencing; Wnt protein; Wnt Signaling Pathway - genetics; clinical diagnosis; missense; deletion; structural variant; skeletal dysplasia
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.61908

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.