Homozygosity Mapping and Exome Sequencing in Consanguineous Pakistani Pedigrees with Autism Spectrum Disorder and Intellectual Disability

Shu Li1,2, Claire S. Leblond2, Sandra Laurent2, Qin Jiang1,2, Sirui Zhou1,2, Dan Spiegelman2, Amirthagowri Ambalavanan2, Mehtab Christian2, Chantal Caron3,4, Baudouin Forgeot d'Arc1,3,4, Saima Rasheed5, Zohair Ali Nanjiani6, Muhammad Qasim Brohi7, Laurent Mottron1,3,4, Guy Rouleau2, Lan Xiong1,2,4

1. Centre de recherche, Institut universitaire en santé mentale de Montréal; 2. Centre de recherche du CHUM; 3. Centre for Excellent in Pervasive and Developmental Problems; 4. Department of Psychiatry, University of Montreal, Canada; 5. Autism Institute, Karachi; 6. Ma Ayesha Memorial Centre, University of Karachi; 7. Sir Cowasjee Jehangir Institute of Psychiatry, Pakistan

Pakistan has the highest rate of consanguineous marriage, as well as a high fertility rate, in the world due to historical, religious, cultural and social reasons. This population characteristic makes Pakistan an excellent location for collecting families for genetic studies, particularly for autosomal recessive traits. In the past few years, with the cooperation from local geneticists and clinicians, we have identified and characterized 6 consanguineous pedigrees with 3-5 affected siblings/first-cousins per pedigree with variable intellectual disability and autism spectrum disorder, which fits with a recessive inheritance pattern. We have carried out classical linkage analysis combined with homozygosity mapping in these 8 ASD/ID pedigrees using high density DNA microarrays. Due to the extreme genetic heterogeneity of ASD/ID, as well as the efficiency and reduced cost of whole exome sequencing, we also performed whole exome sequencing in 2-3 selected affected individuals/pedigree.

We have identified extensive runs of homozygosity region in each individual genome, as well as shared identical-by-descent regions among the affected individuals in each or branch of these 6 pedigrees independently. Combined with whole exome sequencing, we have so far identified a novel frameshift nonsense mutation in the VPS13B gene in one family with 3 affected brothers with atypical Cohen syndrome and autism phenotype. We have also identified another frameshift nonsense mutation in the CC2D1A gene in one family with 5 affected brothers with intellectual disability and autism behaviors. Genetic validation of potential disease-causing mutations in other 6 pedigrees is underway.