WDR35

Inheritance Pattern: AR

Disease ID:MONDO:0013323

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013569

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013323

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009032

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019664

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013569

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013323

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013569

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013569

Submitter: ClinGen

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). Data provided by the ClinGen Prenatal GCEP from April 16, 2025 secondary analysis In summary, there is a prenatal phenotype associated with WDR35-related short-rib thoracic dysplasia as early as late first trimester, evident in six probands demonstrating the gene-disease association, functional alteration in patient cells, protein-protein interactions, and a mouse model. Prenatal findings include narrow thorax (5/6 probands), shortened long bones (4/6), polydactyly (3/6), echogenic kidneys (2/6), hydrops fetalis (1/6), oligohydramnios (1/6), and cardiac abnormality (1/6) (PMIDs: 21473986, 29068549, 34958143, 39252126, 39877340).

Inheritance Pattern: AR

Disease ID:MONDO:0013323

Submitter: ClinGen

The WDR35 gene is located on chromosome 2 at 2p24.1 and encodes IFT121 protein, which forms part of intraflagellar transport (IFT) complex A (IFT-A) that combines with IFT complex B (IFT-B) to form an IFT particle that is important in the assembly and maintenance of cilia. WDR35 was first reported in relation to autosomal recessive cranioectodermal dysplasia (CED) , also known as Sensenbrenner syndrome, a rare multiple anomaly syndrome with distinctive craniofacial findings (forehead bossing, dolichocephaly), metaphyseal dysplasia (short limbs, small thorax), ectodermal anomalies (sparse hair, small and missing teeth, short nails), connective tissue abnormalities (loose skin, joint laxity), retinal dystrophy, and chronic renal and liver disease in 2010 (Gilissen et al., 2010, PMID: 20817137). Additionally, the Craniofacial Malformations GCEP has reviewed the craniofacial findings and agrees with the summary. Evidence supporting this gene-disease relationship includes case-level and experimental data. Biallelic variants in WDR35 (including nonsense, frameshift, splice, and missense variants) were identified in at least 12 patients with clinical features suggestive of CED (PMID: 20817137; Hoffer et al., 2013, PMID: 22486404; Smith et al., 2016, PMID: 26691894; Antony et a., 2017, PMID: 28870638; Walczak-Sztulpa et al., 2017, PMID: 28332779; Walczak-Sztulpa et al., 2018, PMID: 29134781; Walczak-Sztulpa et al., 2021, PMID: 29134781). At least 18 unique variants (missense, nonsense, frameshift, small deletions) have been reported in humans. This gene-disease relationship is supported by protein interaction studies and rescue of phenotype with cell culture models (Caparros-Martin et al., 2015, PMID: 25908617; Takahara et al., 2018, PMID: 29220510). In summary, the WDR35 gene is definitely associated with cranioectodermal dysplasia (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 7.27.2021 (SOP Version 8).