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Significant number out of 2.2 billion vision impairments in the world can be attributed to genetics. The current study is aimed to decipher the genetic basis of Leber congenital Amaurosis (LCA), Anterior Segment dysgenesis (ASD), and Retinitis Pigmentosa (RP), segregating in four large consanguineous Pakistani families. The exome sequencing followed by segregation analysis via Sanger sequencing revealed the LCA phenotypes segregating in families GCUF01 and GCUF04 can be attributed to c.465G>T (p.(Gln155His)) missense and novel c.139_140delinsA p.(Pro47Trhfster38) frameshift variant of AIPL1 and GUCY2D, respectively. The c.1843A>T (p.(Lys615*) truncating allele of MERTK is homozygous in all the affected individuals, presumably suffering with RP, of the GCUF02 family. Meanwhile, co-segregation of the ASD phenotype and the c.289A>G (p.(Ile97Val)) variant of FOXE3 was found in the GCUF06 family. All the identified variants were either absent or present in very low frequencies in the control databases. Our in-silico analyses and 3D molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MERTK, GUCY2D, and FOXE3 were categorized as "pathogenic" or "likely pathogenic", while the missense variant found in AIPL1 was deemed to have "uncertain significance" based upon the variant pathogenicity guidelines from the American College of Medical Genetics and Genomics (ACMG). This paper highlights the genetic diversity of vision disorders in the Pakistani population and reports the identification of four novel mutations in families who segregate clinically heterogeneous eye diseases. Our results give insight into the genotype-phenotype correlations of AIPL1, FOXE3, MERTK, and GUCY2D variants.
Pubmed ID: 32976546 RIS Download
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Software package as multiple sequence alignment tool that uses seeded guide trees and HMM profile-profile techniques to generate alignments between three or more sequences. Accepts nucleic acid or protein sequences in multiple sequence formats NBRF/PIR, EMBL/UniProt, Pearson (FASTA), GDE, ALN/Clustal, GCG/MSF, RSF.
View all literature mentionsData analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsThe National Institute on Deafness and Other Communication Disorders (NIDCD) is one of the Institutes that comprise the National Institutes of Health (NIH). Established in 1988, NIDCD is mandated to conduct and support biomedical and behavioral research and research training in the normal and disordered processes of hearing, balance, smell, taste, voice, speech, and language. The Institute also conducts and supports research and research training related to disease prevention and health promotion; addresses special biomedical and behavioral problems associated with people who have communication impairments or disorders; and supports efforts to create devices which substitute for lost and impaired sensory and communication function. It is estimated that more than 46 million people in the United States suffer some form of disordered communication. NIDCD has focused national attention on disorders of human communication and has contributed to advances in biomedical and behavioral research that will improve the lives of millions of individuals with communication disorders. NIDCD has made important contributions to the body of knowledge needed to help those who experience communication disorders and to advance research in all aspects of human communication. NIDCD accomplishes its mandate through the Division of Intramural Research, which conducts research in laboratories at the NIH, and the Extramural Research Program, a program of research grants, career development awards, individual and institutional research training awards, center grants, and contracts to public and private research institutions and organizations. As a whole, the Institute supports and conducts approximately 600 research projects. The Institute also conducts and supports research and research training in disease prevention and health promotion and the special biomedical and behavioral problems associated with people having communication impairments and disorders. NIDCD''s extramural grant portfolio demonstrates a balance of basic and clinical research. The intramural research program spans a variety of topics, including, but not limited to, the development of a vaccine against otitis media, the identification and characterization of genes responsible for hereditary hearing impairment, genes associated with neoplasms affecting human communication, and treatment of voice disorders.
View all literature mentionsSoftware tool which predicts possible impact of amino acid substitution on structure and function of human protein using straightforward physical and comparative considerations. PolyPhen-2 is new development of PolyPhen tool for annotating coding nonsynonymous SNPs.
View all literature mentionsWeb server as integrated platform for automated protein structure and function prediction. Used for protein 3D structure prediction. Resource for automated protein structure prediction and structure-based function annotation.
View all literature mentionsDatabase that aggregates exome and genome sequencing data from large-scale sequencing projects. The gnomAD data set contains individuals sequenced using multiple exome capture methods and sequencing chemistries. Raw data from the projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects.
View all literature mentionsWeb tool for predicting deleteriousness of variants throughout human genome. Software tool for scoring deleteriousness of single nucleotide variants as well as insertion and deletions variants in human genome.
View all literature mentionsWeb server as integrated platform for automated protein structure and function prediction. Used for protein 3D structure prediction. Resource for automated protein structure prediction and structure-based function annotation.
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