Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France.
J Med Genet. 2023 Dec 21;61(1):36-46. doi: 10.1136/jmg-2023-109170.
Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID).
From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018).
MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%).
MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.
广泛获得临床外显子/基因组测序（ES/GS）使能够识别多个分子诊断（MMD），这是一个长期存在但被低估的概念，由两个或更多因果基因座定义，这些基因座与罕见病患者的表型有关。只有少数几个系列报告了 MMD 发生率（1.8%至 7.1%）。本研究强调了 MMD 在为先天性异常/智力障碍（CA/ID）就诊的大队列个体中的作用日益增加。
从 2014 年到 2021 年，我们的诊断实验室对 880/2658 个导致 CA/ID 病因的 ES 阳性诊断进行了分析。从 ES 数据中前瞻性（2019 年 1 月至 2021 年 12 月）和回顾性（2014 年 3 月至 2018 年 12 月）对 MMD 进行了全面搜索。
在 31/880 名个体（3.5%）中发现了 MMD，这些 MMD 导致了不同的（9/31）或重叠的（22/31）表型，另外 39/880 名个体（4.4%）存在潜在的 MMD。
MMD 在 CA/ID 中很常见，仍然是一个巨大的挑战。当表型部分由初始诊断解释或随着时间的推移异常丰富时，重新分析阳性 ES 数据显得至关重要。最新的临床数据、参考医生的临床专业知识、临床医生和生物学家之间的紧密互动，以及不断增加的基因发现和改进的 ES 生物信息学工具，对于提高识别 MMD 的机会显得更加重要。为患者提供适当的护理和遗传咨询至关重要。
