Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Chaofan Zhang, Angad Jolly, Brian J Shayota, Juliana F Mazzeu, Haowei Du, Moez Dawood, Patricia Celestino Soper, Ariadne Ramalho de Lima, Bárbara Merfort Ferreira, Zeynep Coban-Akdemir, Janson White, Deborah Shears, Fraser Robert Thomson, Andrew Wainwright, Paul Wordsworth, Mike Oldridge, Tracy Lester, Alistair D Calder, Katja Dumic, Siddharth BankaDian Donnai, Shalini N Jhangiani, Lorraine Potocki, Wendy K Chung, Sara Mora, Hope Northrup, Myla Ashfaq, Jill A Rosenfeld, Kati Mason, Lynda C Pollack, Allyn McConkie-Rosell, Wei Kelly, Marie McDonald, Natalie S Hauser, Peter Leahy, Cynthia M Powell, Raquel Boy, Rachel Sayuri Honjo, Fernando Kok, Lucia R Martelli, Vicente Odone Filho, Genomics England Research Consortium, Donna M Muzny, Richard A Gibbs, Jennifer E Posey, Pengfei Liu, James R Lupski, V Reid Sutton

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Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

Original languageEnglish
Article number100074
JournalHuman Genetics and Genomics Advances
Issue number1
Publication statusPublished - 13 Jan 2022


  • DVL2
  • HPO terms
  • genotype-phenotype correlation
  • indel mutations
  • molecular diagnosis
  • quantitative phenotyping cluster heatmap
  • screw-tail breed dogs
  • skeletal dysplasia
  • traits and OMIM clinical synopsis


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