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Exploring genotype-phenotype correlations in glutaric aciduria type 1.
Schuurmans, Imke M E; Dimitrov, Bianca; Schröter, Julian; Ribes, Antonia; de la Fuente, Rubén Pérez; Zamora, Berta; van Karnebeek, Clara D M; Kölker, Stefan; Garanto, Alejandro.
Afiliação
  • Schuurmans IME; Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Dimitrov B; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Schröter J; Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Ribes A; Department of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • de la Fuente RP; Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • Zamora B; Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • van Karnebeek CDM; Division of Pediatric Epileptology, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
  • Kölker S; Section of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, IDIBAPS-CIBERER, Barcelona, Spain.
  • Garanto A; Genetics Department, 12 de Octubre University Hospital, Madrid, Spain.
J Inherit Metab Dis ; 46(3): 371-390, 2023 05.
Article em En | MEDLINE | ID: mdl-37020324
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disease caused by pathogenic variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). We performed an extensive literature search to collect data on GA1 patients, together with unpublished cases, to provide an up-to-date genetic landscape of GCDH pathogenic variants and to investigate potential genotype-phenotype correlation, as this is still poorly understood. From this search, 421 different GCDH pathogenic variants have been identified, including four novel variants; c.179T>C (p.Leu60Pro), c.214C>T (p.Arg72Cys), c.309G>C (p.Leu103Phe), and c.665T>C (p.Phe222Ser).The variants are mostly distributed across the entire gene; although variant frequency in GA1 patients is relatively high in the regions encoding for active domains of GCDH. To investigate potential genotype-phenotype correlations, phenotypic descriptions of 532 patients have been combined and evaluated using novel combinatorial analyses. To do so, various clinical phenotypes were determined for each pathogenic variant by combining the information of all GA1 patients reported with this pathogenic variant, and subsequently mapped onto the 2D and 3D GCDH protein structure. In addition, the predicted pathogenicity of missense variants was analyzed using different in silico prediction score models. Both analyses showed an almost similar distribution of the highly pathogenic variants across the GCDH protein, although some hotspots, including the active domain, were observed. Moreover, it was demonstrated that highly pathogenic variants are significantly correlated with lower residual enzyme activity and the most accurate estimation was achieved by the REVEL score. A clear correlation of the genotype and the clinical phenotype however is still lacking.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encefalopatias Metabólicas / Erros Inatos do Metabolismo dos Aminoácidos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Inherit Metab Dis Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encefalopatias Metabólicas / Erros Inatos do Metabolismo dos Aminoácidos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Inherit Metab Dis Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Holanda