title: Exome sequencing identifies three novel candidate genes implicated in intellectual disability.
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.
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan; Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan.
authors.forename: Zehra
authors.initials: Z
authors.lastname: Agha
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Humaira
authors.initials: H
authors.lastname: Ayub
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Syeda Hafiza Benish
authors.initials: SH
authors.lastname: Ali
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Moeen
authors.initials: M
authors.lastname: Riaz
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan; Department of Biochemistry, Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D059472:Exome; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C117566:ZNF589 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D000217:Acyltransferases; C105599:HHAT protein, human