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Title: Mapping Autosomal Recessive Intellectual Disability in Consanguineous Families
Authors: Ilyas, Muhammad
Keywords: Biological & Medical Sciences
Issue Date: 2020
Publisher: International Islamic University, Islamabad.
Abstract: Intellectual disability (ID) is a neurodevelopmental condition affecting 1–3% of the world‟s population. Genetic factors play a key role causing the congenital limits in intellectual functioning and adaptive behavior. The heterogeneity of ID makes it more problematic for genetic and clinical diagnosis. NGS facilitates the diagnosis of ID families. To accomplish the research objectives of the study, 10 autosomal recessive ID families were analysed. Total numbers of samples were 60, out of those samples 19 were affected individuals. All ten families‟ probands were tested for FMR1 mutation, after exclusion of fragile X syndrome, WES was performed to identify, pathogenic variants, and small insertion/deletions on the affected individual of these families. Analysis of WES results in probands from MR-6 and MR-9 identified potential candidate gene causing ID. In family MR-6, SLITRK3 gene was sharing homozygous truncated mutation (p.E606X) on chromosome 3, in all three affected individual reported to be involved in synapse and neurotransmitter. In family MR-9 SDCBP2 gene also known as syntenin 2 gene sharing homozygosity among all affected probands. However, in both these families functional experiments are in progress to confirm these findings. In family MR-4 WES sequencing analysis identified novel missense mutation (p.P202L) in VPS53, a gene previously reported for ID, as the likely cause of ID in this family as well. The mutation was observed in both affected sibling and obligate carriers but not in healthy member of the family or in the population controls (n=100). In Family MR-5, novel missense homozygous mutation (p.R545C) in NARS gene at chromosome 18 involved in ID was observed in the affected sibling but not in healthy sibling. Family MR-7 exome analysis was performed a novel missense variant (p.H440Y) in GLB1 gene on chromosome 3 was identified and the mutation impact was checked through in-silco analysis and mutation was further conformed by using segregation analysis of the family. All the affected siblings were homozygous and healthy sibling have normal allele. Family MR-8 WES analysis was performed after the data filtration and bioinformatics analysis a novel autosomal recessive missense mutation (p.T320K) in MLC1 gene was identified on chromosome 22. WES analysis of two families‟ (chapter 10) resulted mutation (c.T2C; p.M1T) in SEPSECS gene at chromosome 4 disturbing start codon. SEPSECS gene mutations have been associated with xv delayed development and ID. In families AS105 and AS110, novel nonsense variant (p.Q863X) was identified in PIDD1 gene on chromosome 11 by using whole exome sequencing
Gov't Doc #: 21081
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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