Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes

Abstract

Although copy number changes of 5q31 have been rarely reported, deletions have been associated with some common characteristics, such as short stature, failure to thrive, developmental delay (DD)/intellectual disability (ID), club feet, dislocated hips, and dysmorphic features. We report on three individuals with deletions and two individuals with duplications at 5q31, ranging from 3.6 Mb to 8.1 Mb and 830 kb to 3.4 Mb in size, respectively. All five copy number changes are apparently de novo and involve several genes that are important in developmental pathways, including PITX1, SMAD5, and WNT8A. The individuals with deletions have characteristic features including DD, short stature, club feet, cleft or high palate, dysmorphic features, and skeletal anomalies. Haploinsufficiency of PITX1, a transcription factor important for limb development, is likely the cause for the club feet, skeletal anomalies, and cleft/high palate, while additional genes, including SMAD5 and WNT8A, may also contribute to additional phenotypic features. Two patients with deletions also presented with corneal anomalies. To identify a causative gene for the corneal anomalies, we sequenced candidate genes in a family with apparent autosomal dominant keratoconus with suggestive linkage to 5q31, but no mutations in candidate genes were found. The duplications are smaller than the deletions, and the patients with duplications have nonspecific features. Although development is likely affected by increased dosage of the genes in the region, the developmental disruption appears less severe than that seen with deletion. © 2011 Wiley‐Liss, Inc.

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

“…Our previous molecular screening of the KTCN candidate genes TGFBI, IL9, and PITX1 in 5q31.1-q35.3 locus has not revealed any variants affecting function of these genes in the KTCN-011 family 16 ( Figure 1c). Given that the chromosomal interval mapped by linkage analysis was large in size, only few chosen functional candidate genes were analyzed by Sanger sequencing.…”

“…The previous linkage analyses performed in this Ecuadorian family uncovered a putative KTCN locus on chromosome 5q31.1-q35.3 (two-point NPL LOD = 3.3815). 16 The proximal boundary of the proposed disease haplotype was at D5S471, defined by recombination in KTCN-011-07. Lack of a more distal recombination did not allow specification of a distal border with confidence.…”

“…Lack of a more distal recombination did not allow specification of a distal border with confidence. 16 Interestingly, other suggestive loci on 5q have been identified also for KTCN. 13,[25][26][27] Our 5q31.1-q35.3 linkage region overlapped two of them, 5q31 and 5q32-q33 in the Caucasian/Hispanic and the Southern Italian populations, respectively 13,26 (Figure 1c).…”

“…The pedigrees of Ecuadorian KTCN families have been previously described. 14,16 Briefly, the diagnosis of KTCN was based on visual acuity testing, intraocular pressure assessment, biomicroscopic evaluation, and fundus examination with dilation. In addition, a topographic study (Humphrey Atlas Topograph; Carl Zeiss Meditec, Jena, Germany) with a computer-assisted videokeratoscope was performed in all affected individuals as well as in individuals with a suspected corneal abnormality.…”

“…16 This strategy allowed for a reduction in the number of candidate genes and prioritized potential relevant variants.…”