Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35

Abstract

The ciliary chondrodysplasias represent a group of clinically and genetically heterogeneous disorders that affect skeleton development. Cilia are organelles that project from the surface of many cell types and play an important role during prenatal and postnatal human development. Cranioectodermal dysplasia (Sensenbrenner syndrome, CED) is a ciliopathy primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. To date six genes have been associated with CED: IFT122, WDR35, WDR19, IFT140, IFT43, and IFT52. Prenatal diagnosis of CED is challenging, and genetic testing can facilitate making a correct diagnosis. Here, we report on a family with two male siblings affected by CED: a 3.5 year‐old patient and his 2 year‐old brother. Molecular analysis of the proband at 1 year of age revealed compound heterozygous variants in WDR35: c.3G>A [p.(Met1‐Ala30delinsMetfsTer4)] and c.2522A>T [p.(Asp841Val)]. Ultrasound examination during the second pregnancy revealed an increased nuchal translucency of 4.5 mm and a hypoplastic nasal bone at 12 weeks of gestation. Prenatal diagnostic testing was offered because of an increased risk for chromosomal abnormalities and recurrence risk for CED. Prenatal genetic analysis of a chorionic villus sample detected the WDR35 variants previously identified in the elder brother. This is the first report of a prenatal genetic diagnosis in CED.

Interfamilial clinical variability in four Polish families with cranioectodermal dysplasia and identical compound heterozygous variants in WDR35

“…In addition, a polydactyly, which is not a frequent feature of CED (Lin et al, 2013) was only reported in Patient 5 and cutaneous syndactyly of 2/3 toes was present in Patients 1, 2, and 4. This feature was previously reported in five affected individuals from four other CED families with pathogenic variants in WDR35 (Gilissen et al, 2010;Bacino et al, 2012;Walczak-Sztulpa et al, 2018;Walczak-Sztulpa et al, 2020).…”

“…Our study is unique as all of these CED patients have identical likely pathogenic compound heterozygous WDR35 variants: c.1922T>G encoding p.(Leu641Ter) and c.2522A>T encoding p.(Asp841Val). Notably, both variants have previously been reported as causal variants in CED; p.(Leu641Ter) has been reported as a causal variant in at least two unrelated patients with CED (Hoffer et al, 2013; Li et al, 2015) and p.(Asp841Val) in two other unrelated CED families (Walczak‐Sztulpa et al, 2018; Walczak‐Sztulpa et al, 2020). In other words there are four Polish CED families reported with a heterozygous p.(Leu641Ter) variant and six families with a heterozygous p.(Asp841Val) amino acid substitution, which leads us to believe that both changes are founder variants in the Polish population.…”

“…Renal insufficiency is a very frequent feature, which accounts for ~75% of CED patients with WRD35 gene variants (Antony et al, 2017; Córdova‐Fletes et al, 2018; Walczak‐Sztulpa et al, 2018; Walczak‐Sztulpa et al, 2020). While renal insufficiency was diagnosed in all five herein reported patients, the onset and progression of kidney failure differed between the affected individuals.…”

“…Intra‐ and interfamilial clinical variability have been reported, however, literature on this subject is sparse (Bacino, Dhar, Brunetti‐Pierri, Lee, & Bonnen, 2012; Lin et al, 2013; Walczak‐Sztulpa et al, 2017). Pathogenic variants in genes ( IFT122 , WDR35 , WDR19 , IFT140 , IFT43 , and IFT52 ) that encode components of the ciliary transport machinery have been associated with CED (Walczak‐Sztulpa et al, 2020). Ciliary transport is also known as intraflagellar transport (IFT) and is required for proper assembly, disassembly, and functionality of cilia, which are hair‐like structures projecting from the surface of most of the human cells.…”

“…This protein is an essential part of the so‐called intraflagellar transport complex A (IFT‐A) that regulates transport from the ciliary tip to its base (Antony et al, 2017). So far 17 pathogenic variants in WDR35 in 18 CED patients from 13 families have been reported in literature (Antony et al, 2017; Córdova‐Fletes et al, 2018; Walczak‐Sztulpa et al, 2018; Walczak‐Sztulpa et al, 2020). Although there are various reports on phenotypic differences within families (Bacino et al, 2012; Walczak‐Sztulpa et al, 2017), there are no studies on clinical variability among different families with identical pathogenic variants.…”