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.
Highlights
Intellectual disability (ID), a neurocognitive disorder, is characterized by substantial limitations both in intellectual functioning and in adaptive behavior
These investigations have revealed that only 10% of ID cases are due to X chromosomal defects while the remaining cases are expected to be caused by genetic defects in the autosomes and due to adverse environmental effects such as poor mother health, social deprivation, infections and injuries during prenatal life and hypoxia [6]
The large number of ID genes present a challenge for the identification of the genetic defect in individual families and isolated cases, only a limited number of pathways are emerging whose disruption appears to be shared by groups of ID genes [7]
Summary
Intellectual disability (ID), a neurocognitive disorder, is characterized by substantial limitations both in intellectual functioning and in adaptive behavior. Investigations aiming to unravel the genetic defects initially focused mainly on X-linked ID since male ID patients are overrepresented as compared to females with a ratio of 1:1.3 to 1:1.9 [5]. These investigations have revealed that only 10% of ID cases are due to X chromosomal defects while the remaining cases are expected to be caused by genetic defects in the autosomes and due to adverse environmental effects such as poor mother health, social deprivation, infections and injuries during prenatal life and hypoxia [6]. The large number of ID genes present a challenge for the identification of the genetic defect in individual families and isolated cases, only a limited number of pathways are emerging whose disruption appears to be shared by groups of ID genes [7]
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