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. 2014 Nov 18;9(11):e112687.
doi: 10.1371/journal.pone.0112687. eCollection 2014.

Exome sequencing identifies three novel candidate genes implicated in intellectual disability

Zehra Agha  1 , Zafar Iqbal  2 , Maleeha Azam  3 , Humaira Ayub  3 , Lisenka E L M Vissers  2 , Christian Gilissen  2 , Syeda Hafiza Benish Ali  3 , Moeen Riaz  3 , Joris A Veltman  2 , Rolph Pfundt  2 , Hans van Bokhoven  4 , Raheel Qamar  5
Affiliations

Exome sequencing identifies three novel candidate genes implicated in intellectual disability

Zehra Agha et al. PLoS One. .

Abstract

Intellectual disability (ID) is a major health problem mostly with an unknown etiology. Recently exome sequencing of individuals with ID identified novel genes implicated in the disease. Therefore the purpose of the present study was to identify the genetic cause of ID in one syndromic and two non-syndromic Pakistani families. Whole exome of three ID probands was sequenced. Missense variations in two plausible novel genes implicated in autosomal recessive ID were identified: lysine (K)-specific methyltransferase 2B (KMT2B), zinc finger protein 589 (ZNF589), as well as hedgehog acyltransferase (HHAT) with a de novo mutation with autosomal dominant mode of inheritance. The KMT2B recessive variant is the first report of recessive Kleefstra syndrome-like phenotype. Identification of plausible causative mutations for two recessive and a dominant type of ID, in genes not previously implicated in disease, underscores the large genetic heterogeneity of ID. These results also support the viewpoint that large number of ID genes converge on limited number of common networks i.e. ZNF589 belongs to KRAB-domain zinc-finger proteins previously implicated in ID, HHAT is predicted to affect sonic hedgehog, which is involved in several disorders with ID, KMT2B associated with syndromic ID fits the epigenetic module underlying the Kleefstra syndromic spectrum. The association of these novel genes in three different Pakistani ID families highlights the importance of screening these genes in more families with similar phenotypes from different populations to confirm the involvement of these genes in pathogenesis of ID.

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Conflict of interest statement

Competing Interests: The authors have declared no competing interests exist.

Figures

Figure 1
Figure 1. Pedigree of families (A) MRQ14, (B) MRQ11 and (C) MRQ15.
The segregation of mutation of KMT2B, ZNF589 and HHAT are also in the pedigree. The symbol +/+ represents homozygous ancestral alleles, M/M is for homozygous variant alleles and +/M is for heterozygous carriers. In the panel B, the genotype of the father (III:1) has been deduced.
Figure 2
Figure 2. Photographs of MRQ14 proband.
The photographs demonstrate the classic facial features representative of Kleefstra syndrome.
Figure 3
Figure 3. The sequencing chromatograms of the families MRQ14, MRQ11 and MRQ15.
(A) Shows the panels containing the region with the identified KMT2B mutation in family MRQ14: ancestral (left panel), heterozygous (middle panel) and variant (right panel) (B) shows the region containing the identified ZNF589 mutation in family MRQ11: ancestral (left panel), heterozygous (middle panel) and variant (right panel). (C) shows the de novo variant of HHAT in family MRQ15: ancestral (left panel), heterozygous (right panel).
See this image and copyright information in PMC

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Grants and funding

This work was supported by the COMSATS Institute of Information Technology to RQ. This study was also supported by the European Union's Seventh Framework Program [grant agreement number 241995 project GENCODYS and grant agreement number 223143, project TECHGENE]. None of the funding agencies had any role in study design, data collection and analysis, decision to publish or preparation of the manuscript.