Intrafamilial phenotypic variability in a Polish family with Sensenbrenner syndrome and biallelic WDR35 mutations

Abstract

Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19, and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9‐year‐old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, low‐set ears, and additional ectodermal abnormalities. The patient presented with chronic tubulointerstitial renal disease. She had abnormal echogenicity on renal ultrasound, reduced glomerular filtration, albuminuria and tubular proteinuria, hypocalciuria and hypocitraturia, accompanied by pre‐hypertensive state. This pattern of renal abnormality was regarded as nephronophthisis. Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T>G, p.(Leu641*)) and missense (c.2522A>T, p.(Asp841Val)) variants in WDR35. We present a detailed clinical descriptions of two female siblings showing an intrafamilial phenotypic variability of the disease, and illustrating the potential lethality of CED.

Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations

“…Each of the unaffected parents is a carrier of one of the aforementioned variants. The missense substitution p.(Asp841Val), identified in the proband has been previously described in a heterozygous state in a female Polish patient with Sensenbrenner syndrome (Walczak‐Sztulpa et al, ). The presence of this variant in the second Polish family with CED indicated that the p.(Asp841Val) change could be a founder mutation in the Polish population.…”

“…Less than 60 patients with Sensenbrenner syndrome have been described to date (Antony et al, 2017). The phenotypic spectrum among the patients with Sensenbrenner syndrome is variable, with some intrafamilial and interfamilial differences (Caparr os-Martín et al, 2015;Mill et al, 2011;Walczak-Sztulpa et al, 2017). The biallelic variants identified in six known genes associated with Sensenbrenner syndrome (IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140) are not phenotypically distinct (Arts & Knoers, 2013;Lin et al, 2013).…”

“…The mutated arginine at position 113 is a highly conserved amino acid and is located within the WD40 functional domain of the IFT121 protein. The missense substitution p.(Asp841Val) is a known variant, which has been reported in a female patient with Sensenbrenner syndrome (Walczak-Sztulpa et al, 2017). The PhyloP score of 4.642 and GERP score of 4.85 for an adenine at position 2522 indicated the evolutionary conserved nature of the nucleotide.…”

“…The missense substitution p.(Asp841Val) is a known variant, which has been reported in a female patient with Sensenbrenner syndrome (Walczak‐Sztulpa et al, ). The PhyloP score of 4.642 and GERP score of 4.85 for an adenine at position 2522 indicated the evolutionary conserved nature of the nucleotide.…”

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

“…In this family, the identified CNV also comprises part of the neighboring WDR49 , which encodes a member of the WD repeat protein family. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, and apoptosis (Walczak‐Sztulpa et al., ), but no functional information have been annotated for WDR49 to date. Therefore, the biological effect of WDR49 loss‐of‐function remains to be elucidated.…”