WDR35 variants in a cranioectodermal dysplasia patient with early onset end‐stage renal disease and retinal dystrophy

Abstract

Cranioectodermal dysplasia (CED) is rare heterogeneous condition. It belongs to a group of disorders defined as ciliopathies and is associated with defective cilia function and structure. To date six genes have been associated with CED. Here we describe a 4-year-old male CED patient whose features include dolichocephaly, multi-suture craniosynostosis, epicanthus, frontal bossing, narrow thorax, limb shortening, and brachydactyly. The patient presented early-onset chronic kidney disease and was transplanted at the age of 2 years and 5 months. At the age of 3.5 years a retinal degeneration was diagnosed. Targeted sequencing by NGS revealed the presence of compound heterozygous variants in the WDR35 gene. The variants are a novel missense change in exon 9 p.(Gly303Arg) and a previously described nonsense variant in exon 18 p.(Leu641*). Our findings suggest that patients with WDR35 defects may be at risk to develop early-onset retinal degeneration. Therefore, CED patients with pathogenic variation in this gene should be assessed at least once by the ophthalmologist before the age of 4 years to detect early signs of retinal degeneration.ciliopathy, cranioectodermal dysplasia (Sensenbrenner syndrome), early-onset retinal dystrophy (EORD), end-stage renal disease (ESRD), WDR35 1 | INTRODUCTION Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a clinically and genetically heterogenous disorder that is characterized by skeletal, craniofacial, and ectodermal abnormalities (Tan et al., 2021). CED is one of the ciliary chondrodysplasias. Other phenotypically overlapping disorders included in this group are Mainzer-Saldino syndrome (MZSDS), Jeune asphyxiating thoracic

Ciliary phenotyping in renal epithelial cells in a cranioectodermal dysplasia patient with WDR35 variants

“…The detected variants are a previously described nonsense variant p. (Leu641*) in exon 18 and a novel missense variant p. (Ala1027Thr) in exon 26. The p. (Leu641*) variant is the most frequently reported variant in WDR35 (Hoffer et al, 2013;Li et al, 2015;Zhang et al, 2018b;Brndiarova et al, 2021;Walczak-Sztulpa et al, 2021;Walczak-Sztulpa et al, 2022). Similar to the presented patient, the most frequent combination of variants among CED patients with WDR35 defects is a combination of a missense and a loss of function (LOF) variant present in trans.…”