Allach El Khattabi Laïla, Heide Solveig, Caberg Jean-Hubert, Andrieux Joris, Doco Fenzy Martine, Vincent-Delorme Caroline, Callier Patrick, Chantot-Bastaraud Sandra, Afenjar Alexandra, Boute-Benejean Odile, Cordier Marie Pierre, Faivre Laurence, Francannet Christine, Gerard Marion, Goldenberg Alice, Masurel-Paulet Alice, Mosca-Boidron Anne-Laure, Marle Nathalie, Moncla Anne, Le Meur Nathalie, Mathieu-Dramard Michèle, Plessis Ghislaine, Lesca Gaetan, Rossi Massimiliano, Edery Patrick, Delahaye-Duriez Andrée, De Pontual Loïc, Tabet Anne Claude, Lebbar Aziza, Suiro Lesley, Ioos Christine, Natiq Abdelhafid, Chafai Elalaoui Siham, Missirian Chantal, Receveur Aline, François-Fiquet Caroline, Garnier Pascal, Yardin Catherine, Laroche Cécile, Vago Philippe, Sanlaville Damien, Dupont Jean Michel, Benzacken Brigitte, Pipiras Eva
Cytogenetics department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris; Sorbonne Paris Cité, Paris Descartes University, Medical school, Paris, France.
Department of Development, Reproduction and Cancer, Cochin Research Institute, INSERM U1016, CNRS UMR8104, Paris, France.
J Med Genet. 2020 May;57(5):301-307. doi: 10.1136/jmedgenet-2018-105389. Epub 2018 Oct 4.
The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care.
We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.
Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, and miR-484 seem to have an essential role in the neurocognitive phenotype.
Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.
16p13.11重复的临床意义仍存在争议，但其在发育迟缓（DD）、智力缺陷（ID）或自闭症谱系障碍（ASD）患者中经常被检测到。先前报道的患者特征描述不足或未被描述。缺乏共识性建议导致解读存在差异，给遗传咨询带来挑战。本研究旨在解读基因型与表型的相关性，以改善遗传咨询和患者的医疗护理。
我们回顾性分析了16013例因DD、ID或ASD转诊至12个遗传中心并进行了染色体微阵列分析的患者的数据。对于检测到16p13.11重复的患者，要求其转诊的遗传学家填写一份问卷，以获取患者及其父母详细的临床和遗传数据。
临床特征主要为语言发育迟缓、学习障碍，其次是自闭症谱系障碍。注意到有患心血管疾病的显著风险。约90%的患者从父母一方遗传了该重复。携带该重复的父母中，每四人至少有一人表现出与先证者相似的表型。基因型与表型的相关性显示，重复片段的大小对表型严重程度没有影响。然而， 和miR-484似乎在神经认知表型中起重要作用。
我们的研究表明，在DD/ID/ASD背景下检测到的16p13.11微重复可能具有致病性，并支持 和miR-484在神经认知表型中起重要作用。此外，这表明需要进行心脏评估和随访，并开展一项大型研究以评估主动脉疾病风险。
