Biology subjects

Ahmed P, H.

Publications and source records attributed to Ahmed P, H..

3 recordsLinked to original sources

bioRxiv2021

Genomic sequencing of Lowe syndrome trios reveal a mechanism for the heterogeneity of neurodevelopmental phenotypes

Lowe syndrome is an X-linked recessive monogenic disorder resulting from mutations in the OCRL gene that encodes a phosphatidylinositol 4,5 bisphosphate 5-phosphatase. The disease affects three organs-the kidney, brain and eye and clinically manifests as proximal renal tubule dysfunction, neurodevelopmental delay and congenital cataract. Although Lowe syndrome is a monogenic disorder, there is considerable heterogeneity in clinical presentation; some individuals show primarily renal symptoms with minimal neurodevelopmental impact whereas others show neurodevelopmental defect with minimal renal symptoms. However, the molecular and cellular mechanisms underlying this clinical heterogeneity remain unknown. Here we analyze a Lowe syndrome family in whom affected members show clinical heterogeneity with respect to the neurodevelopmental phenotype despite carrying an identical mutation in the OCRL gene. Genome sequencing and variant analysis in this family identified a large number of damaging variants in each patient. Using novel analytical pipelines and segregation analysis we prioritize variants uniquely present in the patient with the severe neurodevelopmental phenotype compared to those with milder clinical features. The identity of genes carrying such variants underscore the role of additional gene products enriched in the brain or highly expressed during brain development that may be determinants of the neurodevelopmental phenotype in Lowe syndrome. We also identify a heterozygous variant in CEP290, previously implicated in ciliopathies that underscores the potential role of OCRL in regulating ciliary function that may impact brain development. More generally, our findings demonstrate analytic approaches to identify high-confidence genetic variants that could underpin the phenotypic heterogeneity observed in monogenic disorders.

genomics↗

bioRxiv2018

INDEX-db: The Indian Exome Reference database (Phase-I)

Deep sequencing based genetic mapping has greatly enhanced the ability to catalog variants with plausible disease association. The bigger challenge now is to ascertain pathological significance to the array of identified variants to specific disease conditions. Differential selection pressure may impact frequency of genetic variations, and thus the detection of association with disease conditions, across populations. To understand the genotype to phenotype correlations, it thus becomes important to first understand the genetic variation spectrum of a population by creating a reference map. In this study, we report the development of phase I of a new database of coding variations, from the Indian population, with an aim to establish a centralized database of integrated information. This could be useful for researchers involved in studying disease mechanism at the clinical, genetic and cellular level.\n\nDatabase URL: http://indexdb.ncbs.res.in

genomics↗

bioRxiv2018

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

IntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.\n\nMethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.\n\nResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a private mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.\n\nConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.

neuroscience↗