Homozygous indel mutation in CDH11 as the probable cause of Elsahy–Waters syndrome

Abstract

Two sisters from a consanguineous couple were seen in genetics department for facial dysmorphic features and glaucoma. They both had broad foreheads, hypertelorism, megalocorneas, thick eyebrows with synophrys, flat malar regions, broad and bulbous noses, and mild prognathism. Both had glaucoma, younger one also had cataracts and phthisis bulbi. Other findings included bilateral partial cutaneous syndactyly of 2nd and 3rd fingers, history of impacted teeth with dentigerous cyst in the elder one, and intellectual disability (mild and borderline). The sisters were considered to have Elsahy-Waters syndrome. In order to elucidate the underlying molecular cause, sisters and their healthy parents were genotyped by SNP arrays, followed by homozygosity mapping. Homozygous regions were further analyzed by exome sequencing in one affected individual. A homozygous indel variant segregating with the condition was detected in CDH11 (c.1116_1117delinsGATCATCAG, p.(Ile372MetfsTer9)), which was then validated by using Sanger sequencing. CDH11 encodes cadherin 11 (osteo-cadherin) that regulates cell-cell adhesion, cell polarization and migration, as well as osteogenic differentiation. Further experiments revealed that CDH11 expression was decreased in patient-derived fibroblasts as compared to the heterozygous parent and another healthy donor. Immunostaining showed absence of the protein expression in patient fibroblasts. In addition, cell proliferation rate was slow and osteogenic differentiation potential was delayed. We consider that this study reveals loss-of-function mutations in CDH11 as a probable cause of this phenotype. Next generation sequencing in further patients would both prove this gene as causative, and finely delineate this clinical spectrum further contributing in identification of other possibly involved gene(s).

Elsahy–Waters syndrome is caused by biallelic mutations in CDH11

“…Together, these patients and the nature of their mutations strongly support a bona fide disease‐gene link between CDH11 and EWS. Further support of our confirmatory study is the very recent report by Taskiran et al () who identified a homozygous indel variant in CDH11 in two siblings with EWS phenotype (Figure a and b) (Taskiran et al, ).…”

“…A post‐publication matchmaking enabled us to identify a second family with the same phenotype and a novel CDH11 biallelic mutation. Here, we describe the phenotype of the two families in detail and conclude that CDH11 biallelic loss of function is the cause of EWS, which was also recently suggested by Taskiran et al ().…”

“…Gray boxes represent untranslated regions, black boxes coding exons, and black lines introns (the start codon is in exon 3); exons are numbered. Mutations identified in the affected individuals of this study are indicated above, the c.1116_1117delinsGATCATCAG mutation published by Taskiran et al () below the scheme. (b) Domain structure of CDH11 with its five extracellular cadherin domains, the transmembrane domain and the intracellular domain.…”

“…(b) Domain structure of CDH11 with its five extracellular cadherin domains, the transmembrane domain and the intracellular domain. Amino acid alteration identified in patient 2 is shown above, the mutation published by Taskiran et al () below the domain structure. Amino acid (aa) numbers are given.…”

“…Additional features included hypogenitalism, pectus excavatum, and C‐spine fusion, hence the name branchial‐skeletal‐genital syndrome was introduced (MIM 211380) (el‐Sahy & Waters, ). The extreme rarity of the syndrome is evidenced by the near lack of follow‐up case reports apart from detailed description of the original cases by Witkop () and Wedgwood, Curran, Lavelle, and Trott, (), as well as two affected siblings each by Castori et al () and Taskiran et al () (Wedgwood et al, ; Witkop, ). Although suggested to represent a novel entity, the two brothers described by Balci, Kayikcioglu, and Dagli, () probably had Elsahy‐Waters Syndrome (EWS).…”