16p13.11 microduplication in 45 new patients: refined clinical significance and genotype–phenotype correlations

Author:

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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsClinical 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, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.ConclusionOur study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 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.

Publisher

BMJ

Subject

Genetics(clinical),Genetics

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