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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

View ORCID ProfileRicardo Harripaul, Nasim Vasli, Anna Mikhailov, Muhammad Arshad Rafiq, Kirti Mittal, Christian Windpassinger, Taimoor I. Sheikh, Abdul Noor, Huda Mahmood, Samantha Downey, Maneesha Johnson, Kayla Vleuten, Lauren Bell, Muhammad Ilyas, Falak Sher Khan, Valeed Khan, Mohammad Moradi, Muhammad Ayaz, Farooq Naeem, Abolfazl Heidari, Iltaf Ahmed, Shirin Ghadami, Zehra Agha, Sirous Zeinali, Raheel Qamar, Hossein Mozhdehipanah, Peter John, Asif Mir, Muhammad Ansar, Leon French, Muhammad Ayub, View ORCID ProfileJohn B. Vincent
doi: https://doi.org/10.1101/092346
Ricardo Harripaul
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
2Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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Nasim Vasli
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
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Anna Mikhailov
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
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Muhammad Arshad Rafiq
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
3Dept. of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
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Kirti Mittal
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
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Christian Windpassinger
4Institute of Human Genetics, Medical University of Graz, Graz, Austria
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Taimoor I. Sheikh
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
2Institute of Medical Science, University of Toronto, Toronto, ON, Canada
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Abdul Noor
5Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
6Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Huda Mahmood
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
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Samantha Downey
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
7Fleming College, Peterborough, ON, Canada
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Maneesha Johnson
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
7Fleming College, Peterborough, ON, Canada
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Kayla Vleuten
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
7Fleming College, Peterborough, ON, Canada
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Lauren Bell
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
7Fleming College, Peterborough, ON, Canada
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Muhammad Ilyas
8Human Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University, Islamabad, Pakistan
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Falak Sher Khan
9department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
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Valeed Khan
9department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
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Mohammad Moradi
10Qazvin University of Medical Science, Qazvin, Iran
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Muhammad Ayaz
11Lahore Institute of Research & Development, Lahore, Pakistan
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Farooq Naeem
11Lahore Institute of Research & Development, Lahore, Pakistan
12Department of Psychiatry, Queen’s University, Kingston, ON, Canada
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Abolfazl Heidari
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
13Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
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Iltaf Ahmed
14Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
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Shirin Ghadami
15Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Zehra Agha
3Dept. of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
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Sirous Zeinali
15Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Raheel Qamar
3Dept. of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
16Department of Biochemistry, Al-Nafees Medical College, Isra University, Islamabad, Pakistan
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Hossein Mozhdehipanah
17Department of Neurology, Qazvin University of Medical Sciences, Qazvin, Iran
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Peter John
14Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
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Asif Mir
8Human Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University, Islamabad, Pakistan
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Muhammad Ansar
9department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan
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Leon French
18Computational Neurobiology Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
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Muhammad Ayub
11Lahore Institute of Research & Development, Lahore, Pakistan
12Department of Psychiatry, Queen’s University, Kingston, ON, Canada
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John B. Vincent
1Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
2Institute of Medical Science, University of Toronto, Toronto, ON, Canada
19Department of Psychiatry, University of Toronto, Toronto, ON, Canada
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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.

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Posted March 15, 2017.
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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families
Ricardo Harripaul, Nasim Vasli, Anna Mikhailov, Muhammad Arshad Rafiq, Kirti Mittal, Christian Windpassinger, Taimoor I. Sheikh, Abdul Noor, Huda Mahmood, Samantha Downey, Maneesha Johnson, Kayla Vleuten, Lauren Bell, Muhammad Ilyas, Falak Sher Khan, Valeed Khan, Mohammad Moradi, Muhammad Ayaz, Farooq Naeem, Abolfazl Heidari, Iltaf Ahmed, Shirin Ghadami, Zehra Agha, Sirous Zeinali, Raheel Qamar, Hossein Mozhdehipanah, Peter John, Asif Mir, Muhammad Ansar, Leon French, Muhammad Ayub, John B. Vincent
bioRxiv 092346; doi: https://doi.org/10.1101/092346
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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families
Ricardo Harripaul, Nasim Vasli, Anna Mikhailov, Muhammad Arshad Rafiq, Kirti Mittal, Christian Windpassinger, Taimoor I. Sheikh, Abdul Noor, Huda Mahmood, Samantha Downey, Maneesha Johnson, Kayla Vleuten, Lauren Bell, Muhammad Ilyas, Falak Sher Khan, Valeed Khan, Mohammad Moradi, Muhammad Ayaz, Farooq Naeem, Abolfazl Heidari, Iltaf Ahmed, Shirin Ghadami, Zehra Agha, Sirous Zeinali, Raheel Qamar, Hossein Mozhdehipanah, Peter John, Asif Mir, Muhammad Ansar, Leon French, Muhammad Ayub, John B. Vincent
bioRxiv 092346; doi: https://doi.org/10.1101/092346

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