Submission Details

The WDR35 gene is located on chromosome 2 at 2p24.1 and encodes the WD repeat domain 35 protein (also known as IFT121), which forms part of intraflagellar transport (IFT) complex A (IFT-A) that combines with IFT complex B (IFT-B) to form IFT particle that is important in the assembly and maintenance of cilia. WDR35 was first reported in relation to autosomal recessive cranioectodermal dysplasia (CED) type 2, also known as Sensenbrenner syndrome (Gilissen et al., 2010, PMID: 20817137). Mill et al., 2011 (PMID: 21473986) subsequently identified that variants in WDR35 also caused short-rib polydactyly syndrome (SRP), which is an autosomal recessive skeletal ciliopathy characterized by narrow thorax, short ribs, shortened tubular bones, and a trident appearance of the acetabular roof (PMID: 21473986). WDR35-related short-rib thoracic dysplasia (SRTD) encompasses short rib-polydactyly syndrome (SRPS), Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD) which have overlapping features with cranioectodermal dysplasias. These conditions have overlapping phenotypes, which differ by the presence of specific craniofacial features, ectodermal dysplasia, visceral malformation, metaphyseal appearance. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs including the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. The lumping of these terms is consistent with lumping the Skeletal Disorders GCEP has done with other SRTDs.

Evidence supporting this gene-disease relationship includes case-level and experimental data. Biallelic variants in WDR35 (including nonsense, frameshift, splice, and missense variants, small and large deletions) were identified in at least 10 patients with clinical features suggestive of short-rib polydactyly syndrome or Ellis-van Creveld syndrome (PMID: 21473986; Duran et al., 2017, PMID: 28400947; Caparrós-Martín et al., 2015, PMID: 25908617; Zhang et al., 2018, PMID: 29068549). At least 13 unique variants (nonsense, frameshift, splice, and missense variants, small and gross deletions) have been reported in humans. This gene-disease association is supported by non-human model organism studies, protein interaction studies and functional alteration analysis (PMIDs: 21473986; 28400947; 25908617; Reiter et al., 2017, PMID: 28698599). In summary, the WDR35 gene is definitively associated with short-rib thoracic dysplasia (SRTD) that encompasses short rib-polydactyly syndrome (SRPS), Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD) (autosomal recessive inheritance). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 02.23.2022 (SOP Version 8).