title: Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.
abstract: Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: R
authors.identifier: 0000-0001-8948-5830
authors.initials: R
authors.lastname: Harripaul
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Vasli
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Mikhailov
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: M A
authors.initials: MA
authors.lastname: Rafiq
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Mittal
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Windpassinger
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: T I
authors.initials: TI
authors.lastname: Sheikh
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Noor
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Mahmood
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Fleming College, Peterborough, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Downey
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Fleming College, Peterborough, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Fleming College, Peterborough, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Vleuten
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Fleming College, Peterborough, ON, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Bell
authors.affiliation: Human Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University, Islamabad, Pakistan.
authors.forename: M
authors.initials: M
authors.lastname: Ilyas
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: F S
authors.initials: FS
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: V
authors.initials: V
authors.lastname: Khan
authors.affiliation: Qazvin University of Medical Science, Qazvin, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Moradi
authors.affiliation: Lahore Institute of Research & Development, Lahore, Pakistan.
authors.forename: M
authors.initials: M
authors.lastname: Ayaz
authors.affiliation: Lahore Institute of Research & Development, Lahore, Pakistan.|Department of Psychiatry, Queen's University, Kingston, ON, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Naeem
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Heidari
authors.affiliation: Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
authors.forename: I
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Ghadami
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Z
authors.initials: Z
authors.lastname: Agha
authors.affiliation: Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Zeinali
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Department of Biochemistry, Al-Nafees Medical College, Isra University, Islamabad, Pakistan.
authors.forename: R
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Department of Neurology, Qazvin University of Medical Sciences, Qazvin, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Mozhdehipanah
authors.affiliation: Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
authors.forename: P
authors.initials: P
authors.lastname: John
authors.affiliation: Human Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University, Islamabad, Pakistan.
authors.forename: A
authors.initials: A
authors.lastname: Mir
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: M
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Computational Neurobiology Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: L
authors.initials: L
authors.lastname: French
authors.affiliation: Lahore Institute of Research & Development, Lahore, Pakistan.|Department of Psychiatry, Queen's University, Kingston, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Ayub
authors.affiliation: Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: J B
authors.initials: JB
authors.lastname: Vincent
mesh_terms: D000328:Adult; D002874:Chromosome Mapping / Q000379:methods; D003241:Consanguinity; D056915:DNA Copy Number Variations; D005190:Family; D005260:Female; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D007492:Iran; D000073658:Loss of Function Mutation; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D000073359:Exome Sequencing / Q000379:methods