Cranioectodermal Dysplasia 2 (CED2) / Short-Rib Polydactyly Syndromes Type 5 (SRP5) via the WDR35 Gene

Cranioectodermal dysplasia, also known as Sensenbrenner syndrome (CED; OMIM 218330), is clinically and genetically heterogeneous ciliopathic disorder. CED is characterized by craniofacial, skeletal, and ectodermal anomalies (Levin et al. J Pediatr 90:55-61, 1977; Young J Med Genet 26:393-396, 1989; Eke et al. Br J Ophthalmol 80:490-491, 1996; Konstantinidou et al. A J Med Genet 149A:2206-2211, 2009; Walczak-Sztulpa et al. Am J Hum Genet 86:949-956, 2010). CED2 (OMIM 613610) has been reported in two unrelated patients with craniosynostosis, dolichocephaly, narrow thorax with pectus excavatum, short limbs, brachydactyly, and short stature. Facial features included narrow palpebral fissures, telecanthus with hypertelorism, low-set simple ears, everted lower lip, and short neck. (Gilissen et al. Am J Hum Genet 87:418-423, 2010). Other clinical features include teeth abnormalities, joint laxity, inguinal hernia, and webbed fingers, with no evidence of cognitive impairment, renal, or hepatic disease (Gilissen et al. 2010).

The short rib-polydactyly syndromes (SRP) are a group of autosomal recessive lethal skeletal dysplasias characterized by skeletal defects, short ribs, short limbs, polydactyly, and multiple organs anomalies, including heart, kidney, and brain (Mill et al. Am J Hum Genet 88:508-515, 2011). SRP5 (OMIM 614091) is associated with acromesomelic hypomineralization, campomelia and ciliopathy phenotypes, including polysyndactyly, laterality defects, and cystic kidney (Mill et al. 2011). 

CED2 and SRP are inherited in an autosomal recessive manner. Variants in the WDR35 gene cause CED2 or SRP5 (Gilissen et al. Am J Hum Genet 87:418-423, 2010; Mill et al. Am J Hum Genet 88:508-515, 2011). WDR35 gene encodes the WDR35 protein, which contains N-terminal WD40 repeats and C-terminal tetratricopeptide repeats (Gilissen et al. 2010; Mill et al. 2011). The WDR35 protein is a component of the intraflagellar transport complex A, which is involved in the retrograde ciliary transport, an important process for cilia assembly and maintenance (Gilissen et al. 2010; Mill et al. 2011). A mix of missense, nonsense, splicing, frameshift, and gross deletion variants within the WDR35 gene have been reported (Gilissen et al. 2010; Mill et al. 2011).

Sensitivity of this test is currently unknown.

This test provides full coverage of all coding exons of the WDR35 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).