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

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (<i>DVL1</i>, <i>DVL3</i>, <i>FZD2</i>, <i>NXN</i>, <i>ROR2</i>, and <i>WNT5A</i>). 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 <i>DVL2</i>. 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 <i>FZD2</i> variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic <i>NXN</i> variants clustered together with the majority of probands carrying <i>DVL1</i>, <i>DVL2</i>, and <i>DVL3</i> variants, demonstrating no phenotypic distinction between the <i>NXN</i>-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 <i>WNT5A</i>, <i>FZD2</i>, and <i>ROR2</i> 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.