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Genotype, Phenotype and in Silico Pathogenicity Analysis of Hexb Mutations: Panel Based Sequencing for Differential Diagnosis of Gangliosidosis Publisher Pubmed



Mahdieh N1 ; Mikaeeli S1 ; Tavasoli AR2, 3 ; Rezaei Z2 ; Maleki M1 ; Rabbani B1, 3
Authors
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Authors Affiliations
  1. 1. Genetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
  2. 2. Children's Hospital Center, Pediatric Center of Excellence, Tehran University of Medical Center, Tehran, Iran
  3. 3. Growth and Development Research, Tehran University of Medical Sciences, Tehran, Iran

Source: Clinical Neurology and Neurosurgery Published:2018


Abstract

Objectives: Gangliosidosis is an inherited metabolic disorder causing neurodegeneration and motor regression. Preventive diagnosis is the first choice for the affected families due to lack of straightforward therapy. Genetic studies could confirm the diagnosis and help families for carrier screening and prenatal diagnosis. An update of HEXB gene variants concerning genotype, phenotype and in silico analysis are presented. Patients and Methods: Panel based next generation sequencing and direct sequencing of four cases were performed to confirm the clinical diagnosis and for reproductive planning. Bioinformatic analyses of the HEXB mutation database were also performed. Results: Direct sequencing of HEXA and HEXB genes showed recurrent homozygous variants at c.509G>A (p.Arg170Gln) and c.850C>T (p.Arg284Ter), respectively. A novel variant at c.416T>A (p.Leu139Gln) was identified in the GLB1 gene. Panel based next generation sequencing was performed for an undiagnosed patient which showed a novel mutation at c.1602C>A (p.Cys534Ter) of HEXB gene. Bioinformatic analysis of the HEXB mutation database showed 97% consistency of in silico genotype analysis with the phenotype. Bioinformatic analysis of the novel variants predicted to be disease causing. In silico structural and functional analysis of the novel variants showed structural effect of HEXB and functional effect of GLB1 variants which would provide fast analysis of novel variants. Conclusions: Panel based studies could be performed for overlapping symptomatic patients. Consequently, genetic testing would help affected families for patients’ management, carrier detection, and family planning's. © 2018 Elsevier B.V.
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