Title :

Challenging the Traditional Approach for Interpreting Genetic Variants: Lessons from Fabry Disease.

Author(s) :

Germain, Dominique P. [Auteur]
AP-HP. Université Paris Saclay
Université de Versailles Saint-Quentin-en-Yvelines [UVSQ]
Levade, Thierry [Auteur]
Laboratoire de Biochimie [CHU Toulouse]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Centre Hospitalier Universitaire de Toulouse [CHU Toulouse]
Institut Universitaire du Cancer de Toulouse - Oncopole [IUCT Oncopole - UMR 1037]
Hachulla, Eric [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Knebelmann, Bertrand [Auteur]
Service de Néphrologie et Dialyses [CHU Necker]
Lacombe, Didier [Auteur]
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
Centre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
Leguy Seguin, Vanessa [Auteur]
Service de médecine interne et immunologie clinique (SOC 1) [CHU de Dijon]
Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon]
Nguyen, Karine [Auteur]
Hôpital de la Timone [CHU - APHM] [TIMONE]
Département de génétique médicale [Hôpital de la Timone - APHM]
Noël, Esther [Auteur]
Centre Hospitalier Universitaire [Strasbourg] [CHU Strasbourg]
Rabès, J. P. [Auteur]

Journal title :

Clinical Genetics

Abbreviated title :

Clin Genet

Publication date :

2021-12-21

ISSN :

1399-0004

English keyword(s) :

ACMG criteria
experts
Fabry disease
genetic variants
pathogenicity interpretation
variants of unknown significance

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants inGLA.The phenotype varies depending on theGLAvariant, alpha-galactosidase residualactivity, patient's age and gender and, for females, X chromosome ...
Show more >Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants inGLA.The phenotype varies depending on theGLAvariant, alpha-galactosidase residualactivity, patient's age and gender and, for females, X chromosome inactivation. Over1000 variants have been identified, many through screening protocols more suscepti-ble to disclose non-pathogenic variants or variants of unknown significance (VUS).This, together with the non-specificity of some FD symptoms, challenges physiciansattempting to interpretGLAvariants. The traditional way to interpreting pathogenic-ity is based on a combined approach using allele frequencies, genomic databases,global and disease-specific clinical databases, and in silico tools proposed by theAmerican College of Medical Genetics and Genomics. Here, a panel of FD specialistsconvened to study how expertise may compare with the traditional approach. SeveralGLAVUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr,p.Asp313Tyr), were re-analyzed through reviews of patients' charts. The same wasdone for pathogenicGLAvariants with some specificities. Our data suggest that inputof geneticists and physicians with wide expertise in disease phenotypes, prevalence,inheritance, biomarkers, alleles frequencies, disease-specific databases, and literaturegreatly contribute to a more accurate interpretation of the pathogenicity of variants,bringing a significant additional value over the traditional approach.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Submission date :

2024-01-12T05:26:09Z
2024-02-28T10:50:04Z