Thauvin-Robinet Christel, Garde Aurore, Favier Maud, Delanne Julian, Racine Caroline, Rousseau Thierry, Nambot Sophie, Bruel Ange-Line, Moutton Sébastien, Quelin Chloé, Colson Cindy, Brehin Anne-Claire, Guerrot Anne-Marie, Rooryck Caroline, Putoux Audrey, Blanchet Patricia, Odent Sylvie, Schaefer Elise, Boute Odile, Goldenberg Alice, Guichet Agnes, Abel Carine, Morel Godelieve, Fradin Melanie, Isidor Bertrand, Vincent Marie, Francannet Christine, Vera Gabriella, Petit Florence, Nizon Mathilde, Wells Constance, Jeanne Mederic, Deiller Caroline, Ziegler Alban, Godin Manon, Saugier-Veber Pascale, Cassinari Kevin, Blanc Pierre, Simon Emmanuel, Binquet Christine, Duffourd Yannis, Safraou Hana, Denomme-Pichon Anne-Sophie, Vitobello Antonio, Philippe Christophe, Faivre Laurence, Tran-Mau-Them Frédéric, Bourgon Nicolas
Centre de Génétique et Centre de Référence Maladies Rares "Anomalies du Développement et Syndromes Malformatifs de l'Inter-région Est", CHU Dijon Bourgogne, Dijon, France.
FHU-TRANSLAD, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France.
Eur J Hum Genet. 2025 May;33(5):675-682. doi: 10.1038/s41431-025-01823-y. Epub 2025 Apr 4.
In 30-40% of fetuses with structural defects, the causal variant remains undiagnosed after karyotype, chromosomal microarray, and exome sequencing. This study presents the results of a reanalysis of unsolved prenatal ES (pES) cases and investigates how postnatal/postmortem phenotyping contributes to identifying relevant variants. pES data was prospectively reanalyzed for unsolved cases enrolled in the AnDDI-Prénatome cohort study. Postnatal/postmortem data were included with prenatal features using Human Phenotype Ontology terms up to 3 years after pES. The reanalysis involved updating bioinformatic processing and querying raw data using a GREP query. We reanalyzed 58/94 (62%) unsolved pES cases, including 8 variants of unknown significance. Data for clinical examination at birth was available for all live newborns, and postmortem examination was available in 12 terminated fetuses. Additional features were identified at birth in 27/58 cases (44%): 9 terminated fetuses, 2 stillbirths, and 16 live newborns. One diagnosis (SNAPC4) was obtained through a periodic query following recent associations with human disease, and without additional clinical data. Three additional VUS were identified through reanalysis with the addition of new clinical features, illustrating the limited contribution of updated postnatal/postmortem phenotyping in identifying relevant variants after negative pES. In conclusion, the benefit of prospective reanalysis of unsolved pES is limited, even over time. Postnatal genome sequencing may be a more appropriate option than reanalysis with postnatal/postmortem phenotyping to establish a causal diagnosis.
在30%-40%存在结构缺陷的胎儿中，经过核型分析、染色体微阵列分析和外显子组测序后，致病变异仍未得到诊断。本研究展示了对未解决的产前外显子组测序（pES）病例进行重新分析的结果，并调查产后/死后表型分析如何有助于识别相关变异。对纳入AnDDI-Prénatome队列研究的未解决病例的pES数据进行了前瞻性重新分析。使用人类表型本体术语，将产后/死后数据与产前特征相结合，时间跨度最长为pES后3年。重新分析包括更新生物信息学处理，并使用GREP查询对原始数据进行查询。我们重新分析了58/94（62%）例未解决的pES病例，包括8个意义未明的变异。所有存活新生儿均有出生时的临床检查数据，12例终止妊娠的胎儿有死后检查数据。在27/58例（44%）病例中出生时发现了额外特征：9例终止妊娠的胎儿、2例死产和16例存活新生儿。通过近期与人类疾病的关联进行定期查询，在没有额外临床数据的情况下获得了一项诊断（SNAPC4）。通过重新分析并添加新的临床特征，又识别出另外3个意义未明的变异，这表明在pES结果为阴性后，更新的产后/死后表型分析在识别相关变异方面的贡献有限。总之，即使随着时间推移，对未解决的pES病例进行前瞻性重新分析的益处也是有限的。与通过产后/死后表型分析进行重新分析相比，产后基因组测序可能是建立因果诊断的更合适选择。
