Genome-wide CNV analysis uncovers novel pathogenic regions in cohort of five multiplex families with neurodevelopmental disorders

Behjat Ul Mudassir; Mashael Alhumaidi Alotaibi; Nadeem Kizilbash; Daliyah Alruwaili; Anwar Alruwaili; Modhi Alenezi; Zehra Agha

doi:10.1016/j.heliyon.2023.e19718

Genome-wide CNV analysis uncovers novel pathogenic regions in cohort of five multiplex families with neurodevelopmental disorders

Heliyon. 2023 Sep 1;9(9):e19718. doi: 10.1016/j.heliyon.2023.e19718. eCollection 2023 Sep.

Authors

Behjat Ul Mudassir¹, Mashael Alhumaidi Alotaibi², Nadeem Kizilbash³, Daliyah Alruwaili³, Anwar Alruwaili³, Modhi Alenezi³, Zehra Agha¹

Affiliations

¹ Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan.
² Department of Biology, College of Sciences, Jouf University, Sakaka, Saudi Arabia.
³ Department of Medical Laboratory Technology, Northern Border University, Arar, Saudi Arabia.

Abstract

Structural reorganization of chromosomes by genomic duplications and/or deletions are known as copy number variations (CNVs). Pathogenic and disease susceptible CNVs alter gene dosage and its phenotypic expression that often leads to human genetic diseases including Neurological disorders. CNVs affecting same common genes in multiple neurodevelopmental disorders can better explain the shared clinical and genetic aetiology across brain diseases. Our study presents the novel copy number variations in a cohort of five multiplex consanguineous families with intellectual disability, microcephaly, ASD, epilepsy, and neurological syndromic features. Cytoscan HD microarray suite has revealed genome wide deletions, duplications and LOH regions which are co-segregating in the family members for the rare neurodevelopmental syndromic phenotypes. This study identifies 1q21.1 microduplication, 16p11.2 microduplication, Xp11.22 microduplication, 4p12 microdeletion and Xq21.1 microdeletion that significantly contribute to primary disease onset and its progression for the first time in Pakistani families. Our study has potential impact on the understanding of pathogenic genetic predisposition for appearance of complex and heterogeneous neurodevelopmental disorders with otherwise unexplained syndromic features. Identification of altered gene dosage across the genome is helpful in improved diagnosis, better disease management in day-to-day life activities of patients with cognitive impairment and genetic counselling of families where consanguinity is a tradition. Our study will contribute to expand the knowledge of genotype-phenotype expression and future gateways in therapeutics and precision medicine research will be open in Pakistan.