Kessler Luise, Krause Jeremias, Kraft Florian, Amin Asmaa K, Fekete Gyorgy, Lengyel Anna, Pinti Eva, Kovacs Arpad, Lischka Annette, Eggermann Katja, Kurth Ingo, Knopp Cordula, Elbracht Miriam, Begemann Matthias, Eggermann Thomas
Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Clin Genet. 2025 Mar;107(3):278-291. doi: 10.1111/cge.14649. Epub 2024 Dec 12.
To assess the suitability of genome sequencing (GS) as the second step in the diagnostics of patients with the features of 11p15.5-associated imprinting disorders (ImpDis: Silver-Russell syndrome [SRS], Beckwith-Wiedemann syndrome [BWS]), we performed short-read GS in patients negatively tested for imprinting disturbances. Obtaining a genetic diagnosis for patients with the features of these syndromes is challenging due to the clinical and molecular heterogeneity and overlap, and many patients remain undiagnosed after the currently suggested stepwise diagnostic workup. GS was conducted in 48 patients (SRS features: n = 37 and BWS features: n = 11). The detection rate differed markedly between the ImpDis: although a genetic cause could be identified in 51% of patients referred with SRS features, no pathogenic variants were detected in patients with BWS features. Thus, GS substantially improves the diagnostic yield and broadens the spectrum of overlapping disorders with SRS features. Obtaining a precise molecular diagnosis provides the basis for a personalized clinical management. Our findings support the use of GS as a second-tier diagnostic tool for patients with growth disturbances, as it addresses all currently known variant types and shortens the diagnostic odyssey.
为评估基因组测序（GS）作为具有11p15.5相关印记障碍（印记障碍：Silver-Russell综合征 [SRS]、Beckwith-Wiedemann综合征 [BWS]）特征患者诊断第二步的适用性，我们对印记紊乱检测呈阴性的患者进行了短读长GS。由于这些综合征特征患者存在临床和分子异质性及重叠，获得基因诊断具有挑战性，并且许多患者在目前建议的逐步诊断检查后仍未确诊。对48例患者进行了GS（SRS特征：n = 37；BWS特征：n = 11）。印记障碍之间的检测率差异显著：虽然在具有SRS特征的转诊患者中51%可确定遗传原因，但具有BWS特征的患者未检测到致病变异。因此，GS显著提高了诊断率，并拓宽了具有SRS特征的重叠疾病谱。获得精确的分子诊断为个性化临床管理提供了依据。我们的研究结果支持将GS用作生长障碍患者的二级诊断工具，因为它涵盖了所有目前已知的变异类型并缩短了诊断过程。
