title: Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.
abstract: BACKGROUND
  Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.
  
  
  METHODS
  Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.
  
  
  RESULTS
  We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.
  
  
  CONCLUSIONS
  We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.
authors.affiliation: Molecular Neuropsychiatry & Development Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. arshadrafiq68@gmail.com.|Currently at: Department of Physiology and Experimental Medicine (PEM), Hospital for Sick Children, Toronto, ON, Canada. arshadrafiq68@gmail.com.
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.affiliation: CHUM Research Center - Notre Dame Hospital, Montreal, Canada. claire.leblond2@mail.mcgill.ca.|Currently at: Montreal Neurological Institute, McGill University, Montreal, QC, Canada. claire.leblond2@mail.mcgill.ca.
authors.forename: Claire S
authors.initials: CS
authors.lastname: Leblond
authors.affiliation: Department of Biochemistry, Quaid-I-Azam University, and Pakistan Medical Research Council, Islamabad, Pakistan. arif289@gmail.com.
authors.forename: Muhammad Arif Nadeem
authors.initials: MA
authors.lastname: Saqib
authors.affiliation: Molecular Neuropsychiatry & Development Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. akshita.vincent@sickkids.ca.
authors.forename: Akshita K
authors.initials: AK
authors.lastname: Vincent
authors.affiliation: CHUM Research Center - Notre Dame Hospital, Montreal, Canada. amirthagowri.ambalavanan@mail.mcgill.ca.|Currently at: Montreal Neurological Institute, McGill University, Montreal, QC, Canada. amirthagowri.ambalavanan@mail.mcgill.ca.
authors.forename: Amirthagowri
authors.initials: A
authors.lastname: Ambalavanan
authors.affiliation: Department of Biochemistry, Quaid-I-Azam University, and Pakistan Medical Research Council, Islamabad, Pakistan. falakmahmand@gmail.com.
authors.forename: Falak Sher
authors.initials: FS
authors.lastname: Khan
authors.affiliation: The Lahore Institute for Research and Development, Lahore, Punjab, Pakistan. ayyazmalik292@gmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayaz
authors.affiliation: University of Education, Township Campus, College Road, Lahore, Punjab, Pakistan. naseema902000@yahoo.com.
authors.forename: Naseema
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authors.lastname: Shaheen
authors.affiliation: CHUM Research Center - Notre Dame Hospital, Montreal, Canada. dan.spiegelman@mcgill.ca.|Currently at: Montreal Neurological Institute, McGill University, Montreal, QC, Canada. dan.spiegelman@mcgill.ca.
authors.forename: Dan
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authors.lastname: Spiegelman
authors.affiliation: Department of Biotechnology, University of Azad Jammu and Kashmir, P.O. Box 13100, Muzaffarabad, Pakistan. ali.phd.qau@gmail.com.
authors.forename: Ghazanfar
authors.initials: G
authors.lastname: Ali
authors.affiliation: Dept: zoology, University of Education, Lahore, Campus Dera Ghazi Khan, Punjab, Pakistan. amin1158@hotmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Amin-ud-Din
authors.affiliation: CHUM Research Center - Notre Dame Hospital, Montreal, Canada. sandra.laurent2@mcgill.ca.|Currently at: Montreal Neurological Institute, McGill University, Montreal, QC, Canada. sandra.laurent2@mcgill.ca.
authors.forename: Sandra
authors.initials: S
authors.lastname: Laurent
authors.affiliation: Molecular Neuropsychiatry & Development Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. huda.mahmood@mail.utoronto.ca.
authors.forename: Huda
authors.initials: H
authors.lastname: Mahmood
authors.affiliation: CHUM Research Center - Notre Dame Hospital, Montreal, Canada. mehtabsindhi@yahoo.com.
authors.forename: Mehtab
authors.initials: M
authors.lastname: Christian
authors.affiliation: Department of Biochemistry, Quaid-I-Azam University, and Pakistan Medical Research Council, Islamabad, Pakistan. nadiralikerio@yahoo.com.
authors.forename: Nadir
authors.initials: N
authors.lastname: Ali
authors.affiliation: Molecular Neuropsychiatry & Development Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. afennell@gmail.com.
authors.forename: Alanna
authors.initials: A
authors.lastname: Fennell
authors.affiliation: Ma Ayesha Memorial Centre, Karachi, Pakistan. zohair.nanjiani@aku.edu.
authors.forename: Zohair
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authors.lastname: Nanjiani
authors.affiliation: Molecular Neuropsychiatry & Development Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. geraldegger2@gmail.com.|Institute of Human Genetics, Medical University of Graz, Graz, A-8010, Austria. geraldegger2@gmail.com.
authors.forename: Gerald
authors.initials: G
authors.lastname: Egger
authors.affiliation: Hôpital Rivière-des-Prairies, Montreal, Canada. chantal.crn@gmail.com.|Département de Psychiatrie, Université de Montréal, Montreal, Canada. chantal.crn@gmail.com.
authors.forename: Chantal
authors.initials: C
authors.lastname: Caron
authors.affiliation: Department of Biochemistry, Quaid-I-Azam University, and Pakistan Medical Research Council, Islamabad, Pakistan. waqas.ravian.ahmed@gmail.com.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Waqas
authors.affiliation: The Lahore Institute for Research and Development, Lahore, Punjab, Pakistan. ma84@queensu.ca.|Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, ON, Canada. ma84@queensu.ca.
authors.forename: Muhammad
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authors.lastname: Ayub
authors.affiliation: Autism Institute, Karachi, Pakistan. autismaid1@yahoo.com.
authors.forename: Saima
authors.initials: S
authors.lastname: Rasheed
authors.affiliation: Hôpital Rivière-des-Prairies, Montreal, Canada. dismaid1@yahoo.comil.|Département de Psychiatrie, Université de Montréal, Montreal, Canada. dismaid1@yahoo.comil.|Research Centre, Montreal Mental Health University Institute, 7331, rue Hochelaga, Montréal, QC, H1N 3 V2, Canada. dismaid1@yahoo.comil.
authors.forename: Baudouin
authors.initials: B
authors.lastname: Forgeot d'Arc
authors.affiliation: Département de Psychiatrie, Université de Montréal, Montreal, Canada. amelie.johnson@umontreal.ca.|Research Centre, Montreal Mental Health University Institute, 7331, rue Hochelaga, Montréal, QC, H1N 3 V2, Canada. amelie.johnson@umontreal.ca.
authors.forename: Amelie
authors.initials: A
authors.lastname: Johnson
authors.affiliation: The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, Canada. joyce.so@utoronto.ca.|The Centre for Addiction and Mental Health, Toronto, Canada. joyce.so@utoronto.ca.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. joyce.so@utoronto.ca.
authors.forename: Joyce
authors.initials: J
authors.lastname: So
authors.affiliation: Sir Cowasji Jehangir Institute of Psychiatry, Hyderabad, Sindh, Pakistan. qbrohi@gmail.com.
authors.forename: Muhammad Qasim
authors.initials: MQ
authors.lastname: Brohi
authors.affiliation: Hôpital Rivière-des-Prairies, Montreal, Canada. laurent.mottron@umontreal.ca.|Département de Psychiatrie, Université de Montréal, Montreal, Canada. laurent.mottron@umontreal.ca.|Research Centre, Montreal Mental Health University Institute, 7331, rue Hochelaga, Montréal, QC, H1N 3 V2, Canada. laurent.mottron@umontreal.ca.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mottron
authors.affiliation: Department of Biochemistry, Quaid-I-Azam University, and Pakistan Medical Research Council, Islamabad, Pakistan. mansar_76@yahoo.com.
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authors.lastname: Ansar
authors.affiliation: Molecular Neuropsychiatry & Development Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada. john.vincent@camh.ca.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada. john.vincent@camh.ca.
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.affiliation: CHUM Research Center - Notre Dame Hospital, Montreal, Canada. lan.xiong@umontreal.ca.|Département de Psychiatrie, Université de Montréal, Montreal, Canada. lan.xiong@umontreal.ca.|Research Centre, Montreal Mental Health University Institute, 7331, rue Hochelaga, Montréal, QC, H1N 3 V2, Canada. lan.xiong@umontreal.ca.
authors.forename: Lan
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mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics / Q000473:pathology*; D001483:Base Sequence; D002658:Developmental Disabilities / Q000145:classification / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D005260:Female; D005385:Fingers / Q000002:abnormalities* / Q000473:pathology; D005808:Genes, Recessive; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008831:Microcephaly / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D009216:Myopia / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D009765:Obesity / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D012162:Retinal Degeneration; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C475722:VPS13B protein, human; D033921:Vesicular Transport Proteins