Journal Article

Homozygosity Mapping and Targeted Sanger Sequencing Reveal Genetic Defects Underlying Inherited Retinal Disease in Families from Pakistan

Maria, Maleeha, Ayub, Humaira, Ahmed, Waqas, Ajmal, Muhammad, Ali, Syeda Hafiza Benish, Ahmad, Shakeel, Siddiqui, Sorath Noorani, Shah, Syed Tahir Abbas, Ali, Liaqat, Haer-Wigman, Lonneke, Cremers, Frans P. M., Khan, Muhammad Imran, Azam, Maleeha, Khan, Yar Muhammad, Waheed, Nadia Khalida, Micheal, Shazia, Qamar, Raheel, Mustafa, Bilal, den Hollander, Anneke I., Hussain, Alamdar, Collin, Rob W. J.

2015

Overview

Homozygosity mapping has facilitated the identification of the genetic causes underlying inherited diseases, particularly in consanguineous families with multiple affected individuals. This knowledge has also resulted in a mutation dataset that can be used in a cost and time effective manner to screen frequent population-specific genetic variations associated with diseases such as inherited retinal disease (IRD). We genetically screened 13 families from a cohort of 81 Pakistani IRD families diagnosed with Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), congenital stationary night blindness (CSNB), or cone dystrophy (CD). We employed genome-wide single nucleotide polymorphism (SNP) array analysis to identify homozygous regions shared by affected individuals and performed Sanger sequencing of IRD-associated genes located in the sizeable homozygous regions. In addition, based on population specific mutation data we performed targeted Sanger sequencing (TSS) of frequent variants in AIPL1, CEP290, CRB1, GUCY2D, LCA5, RPGRIP1 and TULP1, in probands from 28 LCA families. Homozygosity mapping and Sanger sequencing of IRD-associated genes revealed the underlying mutations in 10 families. TSS revealed causative variants in three families. In these 13 families four novel mutations were identified in CNGA1, CNGB1, GUCY2D, and RPGRIP1. Homozygosity mapping and TSS revealed the underlying genetic cause in 13 IRD families, which is useful for genetic counseling as well as therapeutic interventions that are likely to become available in the near future.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Blindness / Congenital diseases / Consanguinity / Defects / DNA Mutational Analysis / Dystrophy / Female / Gene mapping / Gene sequencing / Gene therapy / Genes / Genetic counseling / Genetic diversity / Genetic screening / Genetics / Genotype / Guanylate cyclase 1 / Hereditary diseases / Homozygosity / Homozygote / Hospitals / Humans / Information technology / Leber congenital amaurosis / Leber Congenital Amaurosis - epidemiology / Leber Congenital Amaurosis - genetics / Life sciences / Male / Mapping / Mutation / Nyctalopia / Pakistan - epidemiology / Pedigree / Photoreceptors / Polymorphism / Polymorphism, Single Nucleotide / Population genetics / Retina / Retina - metabolism / Retina - pathology / Retinal Diseases - epidemiology / Retinal Diseases - genetics / Retinitis / Retinitis pigmentosa / Retinitis Pigmentosa - epidemiology / Retinitis Pigmentosa - genetics / Single-nucleotide polymorphism / Stationary night blindness / Sustainable development / Therapeutic applications