Genomic imbalances defining novel intellectual disability associated loci

Fátima Lopes†,
Fátima Torres†,
Gabriela Soares,
Mafalda Barbosa,
João Silva,
Frederico Duque,
Miguel Rocha,
Joaquim Sá,
Guiomar Oliveira,
Maria João Sá,
Teresa Temudo,
Susana Sousa,
Carla Marques,
Sofia Lopes,
Catarina Gomes,
Gisela Barros,
Arminda Jorge,
Felisbela Rocha,
Cecília Martins,
Sandra Mesquita,
Susana Loureiro,
Elisa Maria Cardoso,
Maria José Cálix,
Andreia Dias,
Cristina Martins,
Céu R. Mota,
Diana Antunes,
Juliette Dupont,
Sara Figueiredo,
Sónia Figueiroa,
Susana Gama-de-Sousa,
Sara Cruz,
Adriana Sampaio,
Paul Eijk,
Marjan M. Weiss,
Bauke Ylstra,
Paula Rendeiro,
Purificação Tavares,
Margarida Reis-Lima,
Jorge Pinto-Basto,
Ana Maria Fortuna and
Patrícia MacielEmail author View ORCID ID profile

†Contributed equally

Orphanet Journal of Rare Diseases201914:164

https://doi.org/10.1186/s13023-019-1135-0

Received: 16 January 2019
Accepted: 12 June 2019
Published: 5 July 2019

Abstract

Background

High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID).

Results

We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed.

Conclusions

Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.