RESUMO
To provide a comprehensive data on the prevalence of mutations in Leber congenital amaurosis (LCA) candidate genes from a larger Indian cohort. Ninety-two unrelated subjects were recruited after complete ophthalmic examination and informed consent. Targeted re-sequencing of 20 candidate genes was performed using Agilent HaloPlex target enrichment assay and sequenced on Illumina MiSeq platform. The data were analyzed using standard bioinformatics pipeline, variants annotated, validated and segregated. Genotype-phenotype correlation was performed for the mutation-positive cases. Targeted next generation sequencing (NGS) for the 20 candidate genes generated data with an average sequence coverage and depth of 99.03% and 134X, respectively. Mutations were identified in 61% (56/92) of the cases, which were validated, segregated in the families and absent in 200 control chromosomes. These mutations were observed in 14/20 candidate genes and 39% (21/53) were novel. Distinct phenotypes were observed with respect to genotypes. To our knowledge, this study presents the first comprehensive mutation spectrum of LCA in a large Indian cohort. The mutation-negative cases indicate scope for finding novel candidate gene(s) although mutations in deep intronic and regulatory regions cannot be ruled out.
Assuntos
Exoma/genética , Perfil Genético , Sequenciamento de Nucleotídeos em Larga Escala , Amaurose Congênita de Leber/genética , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Índia , Lactente , Recém-Nascido , Amaurose Congênita de Leber/fisiopatologia , Masculino , Mutação/genética , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Gene mapping of inherited ophthalmic diseases such as congenital cataracts, retinal degeneration, glaucoma, age-related macular degeneration, myopia, optic atrophy, and eye malformations has shed more light on the disease pathology, identified targets for research on therapeutics, earlier detection, and treatment options for disease management and patient care. This article details the different approaches to gene identification for both Mendelian and complex eye disorders.
Assuntos
Mapeamento Cromossômico/métodos , Oftalmopatias Hereditárias/genética , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Ligação Genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/métodosRESUMO
Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder which represents rod photoreceptor dysfunction or signal transmission defect from photoreceptors to adjacent bipolar cells. Patients displaying photoreceptor dysfunction show a Riggs-electroretinogram (ERG) while patients with a signal transmission defect show a Schubert-Bornschein ERG. The latter group is subdivided into complete or incomplete (ic) CSNB. Only few CSNB cases with Riggs-ERG and only one family with a disease-causing variant in SLC24A1 have been reported. Whole-exome sequencing (WES) in a previously diagnosed icCSNB patient identified a homozygous nonsense variant in SLC24A1. Indeed, re-investigation of the clinical data corrected the diagnosis to Riggs-form of CSNB. Targeted next-generation sequencing (NGS) identified compound heterozygous deletions and a homozygous missense variant in SLC24A1 in two other patients, respectively. ERG abnormalities varied in these three cases but all patients had normal visual acuity, no myopia or nystagmus, unlike in Schubert-Bornschein-type of CSNB. This confirms that SLC24A1 defects lead to CSNB and outlines phenotype/genotype correlations in CSNB subtypes. In case of unclear clinical characteristics, NGS techniques are helpful to clarify the diagnosis.
Assuntos
Oftalmopatias Hereditárias/genética , Genes Recessivos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Miopia/genética , Cegueira Noturna/genética , Trocador de Sódio e Cálcio/genética , Sequência de Aminoácidos , Sequência de Bases , Eletrorretinografia , Exoma/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/fisiopatologia , Saúde da Família , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Homozigoto , Humanos , Masculino , Miopia/diagnóstico , Miopia/fisiopatologia , Cegueira Noturna/diagnóstico , Cegueira Noturna/fisiopatologia , Linhagem , Homologia de Sequência de AminoácidosRESUMO
Hereditary cancers are thought to account for around 5% of cancers, particularly breast/ovarian and colorectal cancers. In India there is a paucity of data on hereditary cancers and the mutations in some of the common genes linked to hereditary cancers, such as BRCA1, BRCA2, hMSH2 and hMLH1. The country's first comprehensive hereditary cancer clinic was established in February 2002. The article describes the organization and running of the Clinic. It also discusses some of the social issues relevant to the given population in running the Hereditary Cancer Clinic.
