TY - JOUR
T1 - Exploring genotype–phenotype correlations in glutaric aciduria type 1
AU - Schuurmans, Imke M. E.
AU - Dimitrov, Bianca
AU - Schröter, Julian
AU - Ribes, Antonia
AU - de la Fuente, Rubén P. rez
AU - Zamora, Berta
AU - van Karnebeek, Clara D. M.
AU - Kölker, Stefan
AU - Garanto, Alejandro
N1 - Funding Information: The authors gratefully acknowledge Dr. Hanka Venselaar (Radboudumc, Nijmegen NL) for the assistance with the 3D protein analysis, Dr. Karlien Coene for initial discussions and Dr. Heiko Brennenstuhl for the assistance in the variant pathogenicity analysis. The authors also like to acknowledge Familias GA1 foundation and all patients that contributed to the Spanish registry, as well as all the professionals of the different Spanish hospitals that participated in the data collection. In addition, the authors would like to thank Emma Dyke for reviewing the manuscript. Funding Information: Collaboration for this paper has been initiated by the Changing rare disorders of lysine metabolism (CHARLIE) consortium (EJPRD grant no: 825575 awarded to Clara D.M. van Karnebeek and Bianca Dimitrov, in collaboration with Antonia Ribes, Stefan Kölker, and Alejandro Garanto). Imke M.E. Schuurmans was supported by an internal Radboudumc PhD grant provided by the Radboud Institute for Molecular Life Sciences to Clara D.M. van Karnebeek and Alejandro Garanto. The authors also acknowledge the support of Generalitat de Catalunya SGR 1428 and CIBERER that is an initiative of the ISCIII, Spain (Antonia Ribes), and the Fundación Mutua Madrileña (2019/0117) to Berta Zamora. The funding organizations provided unrestricted grants and had no role in the design or conduct of this research. Publisher Copyright: © 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2023/5
Y1 - 2023/5
N2 - 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 We performed an extensive literature search to collect data on GA1 patients, together with unpublished cases, to provide an up-to-date genetic landscape of GCDH pathogenic variants and to investigate potential genotype-phenotype correlation, as this is still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.
AB - 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.
KW - GCDH variants
KW - glutaric aciduria type 1
KW - lysine catabolism disorder
KW - pathogenicity score
KW - phenotype-genotype correlation
UR - http://www.scopus.com/inward/record.url?scp=85153320401&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12608
DO - https://doi.org/10.1002/jimd.12608
M3 - Article
C2 - 37020324
SN - 0141-8955
VL - 46
SP - 371
EP - 390
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 3
ER -