Novel variants underlying autosomal recessive intellectual disability in Pakistani consanguineous families

• Published in: BMC medical genetics Vol. 21; no. 1; p. 59
• Main Authors: Ilyas, Muhammad, Efthymiou, Stephanie, Salpietro, Vincenzo, Noureen, Nuzhat, Zafar, Faisal, Rauf, Sobiah, Mir, Asif, Houlden, Henry
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24-03-2020; BioMed Central; BMC
• Subjects: Age; beta-Galactosidase - genetics; Bioinformatics; Causes of; Child; Child, Preschool; Cognitive ability; Computational biology; Consanguinity; Diagnosis; Disabilities; Diseases; DNA sequencing; Families & family life; Family; Female; Gene mapping; Genes; Genes, Recessive - genetics; Genetic aspects; Genetic diversity; Genetic Heterogeneity; Genetic Testing; Genetic variation; Genomes; GLB1 gene; Health aspects; Homozygote; Humans; Intellectual disabilities; Intellectual disability; Intellectual Disability - complications; Intellectual Disability - genetics; Intellectual Disability - pathology; Intelligence; Male; Medical imaging; Medical research; Membrane Proteins - genetics; MLC1 gene; Neurodevelopmental disorders; Neurodevelopmental Disorders - complications; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - pathology; Novels; Pakistan - epidemiology; Patients; Pedigree; Polymorphism, Genetic; Studies; Vesicular Transport Proteins - genetics; VPS53 gene; Whole Exome Sequencing; Pakistan; MLC1 gene; GLB1 gene; VPS53 gene; Intellectual disability; Whole exome sequencing
• ISSN: 1471-2350; 1471-2350
• DOI: 10.1186/s12881-020-00998-z

Intellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID.
To determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis.
Rare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families.
This study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani families.