El Chehadeh Salima, Heide Solveig, Quélin Chloé, Rio Marlène, Margot Henri, Geneviève David, Isidor Bertrand, Goldenberg Alice, Guégan Caroline, Lesca Gaëtan, Willems Marjolaine, Ormières Clothilde, Caumes Roseline, Busa Tiffany, Bonneau Dominique, Guerrot Anne-Marie, Marey Isabelle, Vera Gabriella, Marzin Pauline, Philippe Anaïs, Garde Aurore, Coubes Christine, Vincent Marie, Michaud Vincent, Mignot Cyril, Charles Perrine, Sigaudy Sabine, Edery Patrick, Lacombe Didier, Boland Anne, Nowak Frédérique, Bouctot Marion, Humbert-Asensio Marie-Laure, Simon Alban, Chennen Kirsley, Sabour Niki, Delmas Christelle, Nicolas Gaël, Saugier-Veber Pascale, Lecoquierre François, Cassinari Kévin, Keren Boris, Courtin Thomas, De Sainte Agathe Jean-Madeleine, Malan Valérie, Barcia Giulia, Tran Mau-Them Frédéric, Safraou Hana, Philippe Christophe, Thévenon Julien, Chatron Nicolas, Januel Louis, Piton Amélie, Haushalter Virginie, Gérard Bénédicte, Lejeune Catherine, Faivre Laurence, Sanlaville Damien, Héron Delphine, Odent Sylvie, Nitschké Patrick, Schluth-Bolard Caroline, Lyonnet Stanislas, Deleuze Jean-François, Binquet Christine, Dollfus Hélène
Service de Génétique Médicale, Institut de Génétique Médicale D'AlsaceINSERM UMRS_1112Hôpitaux Universitaires de Strasbourg, CRBS, 1 Rue Eugène Boeckel, Strasbourg, 67000, France.
Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM UMRS_1112, Université de Strasbourg, CRBS, Strasbourg, France.
Genome Med. 2025 Oct 3;17(1):110. doi: 10.1186/s13073-025-01527-4.
Intellectual disability (ID) is the leading cause of patient referral to medical genetic departments in French academic hospitals. Whole genome sequencing (WGS) as a first diagnostic approach is expected to achieve a higher diagnostic yield than the French national reference strategies (RefStrategy) (fragile X expansion testing, chromosomal microarray analysis, and 44 ID genes panel), given its broad and more homogeneous coverage, its ability to identify copy number, structural and intergenic/deep intronic events.
DEFIDIAG is a national, prospective pilot investigation, carried out in the framework of the French initiative for genomic medicine (Plan France Médecine Génomique 2025), aimed at comparing the diagnostic yield of WGS trio analysis (WGS-trio) (index case, father, mother) with the RefStrategy in real-life conditions of clinical and laboratory workflows. Both strategies were applied in a blinded fashion in 1239 ID probands (50% were already-tested, 50% were never-tested) with no definitive genetic diagnosis. Among them, a subgroup of 187 patients were randomized to undergo WGS-solo (proband only) in addition to WGS-trio and RefStrategy.
Four hundred forty two likely pathogenic/pathogenic single-nucleotide variants were identified (for 231 genes) as well as 171 variants of uncertain significance warranting clinical or functional reassessment for a potential reclassification (VUS +) (for 142 genes), 79 likely pathogenic/pathogenic copy number variants and 10 likely pathogenic/pathogenic structural variants. The diagnostic yield for likely pathogenic/pathogenic variants increased from 17.3% with the RefStrategy to 41.9% with WGS-trio in the never-tested patient cohort. An increase of 13.9% was observed in all categories by adding the VUS + , thus raising the yield to 56% for WGS-trio. Overall, WGS-solo enabled the identification of likely pathogenic/pathogenic variants in 29.9% of cases (increasing to 41.1% when including VUS +) compared to 21.9% with the RefStrategy. In addition, following recent reports of de novo variants in the non-coding spliceosomal RNU4-2 gene as a common cause of ID, this gene was subsequently analyzed, leading to the identification of pathogenic de novo variants in 7 patients.
As a first line test for ID diagnosis, WGS (including for solo situations) proved to be more effective than the reference strategy, in the context of real-life hospital settings in France.
Prospectively registered with ClinicalTrials.gov under the identifier NCT04154891 (07/11/2019).
智力障碍（ID）是法国学术医院患者转诊至医学遗传科的主要原因。全基因组测序（WGS）作为一种首要诊断方法，鉴于其广泛且更均匀的覆盖范围、识别拷贝数、结构以及基因间/内含子深处事件的能力，预计能比法国国家参考策略（RefStrategy）（脆性X扩增检测、染色体微阵列分析以及44个ID基因检测板）获得更高的诊断率。
DEFIDIAG是一项全国性的前瞻性试点研究，在法国基因组医学倡议（2025年法国医学基因组计划）框架内开展，旨在比较WGS三联体分析（WGS - trio）（先证者、父亲、母亲）与RefStrategy在临床和实验室工作流程的实际情况下的诊断率。两种策略均以盲法应用于1239例未明确基因诊断的ID先证者（50%已接受检测，50%从未接受检测）。其中，187例患者的亚组被随机分配除接受WGS - trio和RefStrategy外还接受WGS单样本分析（仅先证者）。
共鉴定出442个可能致病/致病的单核苷酸变异（涉及231个基因）以及171个意义未明的变异（VUS +）（涉及142个基因），这些变异需要进行临床或功能重新评估以进行潜在的重新分类，79个可能致病/致病的拷贝数变异和10个可能致病/致病的结构变异。在从未接受检测的患者队列中，可能致病/致病变异的诊断率从RefStrategy的17.3%增至WGS - trio的41.9%。通过加入VUS +，所有类别均观察到增加了13.9%，从而使WGS - trio的诊断率提高到56%。总体而言，与RefStrategy的21.9%相比，WGS单样本分析在29.9%的病例中鉴定出可能致病/致病变异（包括VUS +时增至41.1%）。此外，继最近报道非编码剪接体RNU4 - 2基因中的新生变异是ID的常见病因之后，随后对该基因进行了分析，结果在7例患者中鉴定出致病的新生变异。
在法国实际医院环境中，作为ID诊断的一线检测方法，WGS（包括单样本情况）被证明比参考策略更有效。
在ClinicalTrials.gov上前瞻性注册，标识符为NCT04154891（2019年11月7日）。
