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Sur le plan international, les recommandations émises par l'ACMG-AMP (American College of, Medical Genetics & the Association for Molecular Pathology, 2016. ,
, Puisque l'interprétation des variants constitue une étape essentielle et critique pour l'homogénéisation inter-laboratoire des rendus de résultats
, AG a souhaité initier un Groupe de Travail spécifique dans l'objectif d'aboutir à un consensus national, dans le contexte actuel de la mise en place prochaine des premières plateformes PFMG2025
, DefiScience (Filière de Santé Maladies Rares du Développement Cérébral et de la Déficience Intellectuelle) et FILNEMUS (Filière de Santé des Maladies Rares Neuromusculaires), où des travaux d'homogénéisation de l'interprétation des variants de séquence ont été débutés, et seront disponibles comme base de travail. Les recommandations ACMG-AMP étant déjà largement appliquées par de nombreux laboratoires de diagnostic génétique en France, l'objectif qui nous semble à la fois important et réalisable à court terme serait une adoption officielle, Cette problématique a été abordée en particulier dans le cadre des commissions de diagnostic génétique des FNMR (Filières de soin Nationales de Maladies Rares ) AnDDi-Rares (Filière de Santé Anomalies du Développement et Déficience intellectuelle de Causes Rares)
, Pour cette raison, un groupe de travail représentatif des différentes parties constituantes du Réseau NGS-Diag a été mis en place pour procéder selon la démarche suivante
, Elaboration du présent document de recommandations en français, issu d'un document très complet déjà réalisé par l'équipe de Rouen
, et contact/lien à établir avec l'ACMG (notamment pour suivre les évolutions des recommandations de l'ACMG, et d'être associé à des versants d'évolution de ces recommandations). A ce stade aussi, des interactions avec le CREFIX (Centre de référence, d'innovation, d'expertise et de transfert)
, Relai des guidelines au sein des FNMR/réseaux d'oncogénétique, et travaux spécifiques éventuels au niveau des FNMR/réseaux d'oncogénétique (échange de fichiers vcf, spécifications si nécessaire de certains items de l'interprétation
, Il peut s'agir d'ajouter des arguments d'interprétation pour les métaboliciens (poids des dosages enzymatiques), les oncogénéticiens (poids des analyses somatiques), les cardiogénéticiens, etc? Ces recommandations
La 2 ème version de ce document prend en compte les modifications des recommandations ACMG publiées depuis la sortie de la première version de ce document (NGSDIAG_001), 2018. ,
, et les recommandations gène-spécifiques élaborées par des Groupes d'experts du réseau ClinGen ou autres experts dans le domaine, vol.2, 2018.
Un autre point important qui n'était pas abordé dans la première version de ce document est le choix des gènes sur les panels diagnostiques. L'objectif d'un panel de gènes à visée diagnostique est de maximiser la sensibilité clinique et de minimiser les explorations inutiles ainsi que le stress secondaires à la découverte des variants dont la signification clinique est incertaine, Les recommandations récentes de American College of Medical Genetics and Genomics (ACMG) visent à clarifier quels gènes sont adaptés pour être inclus dans les panels diagnostiques, 2019. ,
, Si l'indication est le diagnostic des cas cliniquement complexes, les GUS (Gene of uncertain significance) peuvent être inclus. Dans ce cas, le consentement type exome/génome est requis. De plus, dans le compte rendu, il est nécessaire de clairement séparer les variants identifiés dans les GUS des variants identifiés dans les GAD. La classification maximale attribué à un variant identifié dans un gène sans lien gène-pathologie établie (GUS) ne
, Plus le nombre de sujets testés attestant de la co-ségrégation du génotype avec le phénotype est important ou plus les sujets testés sont éloignés dans l'arbre généalogique, plus l'argument peut avoir un poids élevé. Afin de préciser ce critère, il a été proposé (Jarvik and Browning, Les nouveaux recommandations de groupe de travail ClinGen SVI propose le système de calcul des scores PS2/PM6(SVI_Recommendation_for_PS2_and_PM6_criteria, 2016.
, En fonction de la probabilité N calculée, une pondération associée est proposée de la manière suivante : Données issues d'une seule famille : N ? 1/32 : argument fort
, N ? 1/16 : argument moyen (PM)
, N ? 1/8 : argument faible (PP)
, Données issues de plusieurs familles : N ? 1/16 : argument fort
, N ? 1/8 : argument moyen (PM)
, N ? 1/4 : argument faible (PP)
, Des exemples de calcul pour la détermination de la probabilité « N », selon les différents modes de transmission, sont donnés dans l'article de Jarvik et Browning (Jarvik and Browning, Am J Hum Genet, 2016.
, Une façon plus simple d'évaluer la ségrégation est d'utiliser les tableaux avec des LOD scores précalculés, Cette approche est adoptée par les groupes ClinGen (les instructions détaillées disponibles à
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