TY - JOUR
T1 - Genomic imbalances defining novel intellectual disability associated loci
AU - Lopes, F. tima
AU - Torres, F. tima
AU - Soares, Gabriela
AU - Barbosa, Mafalda
AU - Silva, João
AU - Duque, Frederico
AU - Rocha, Miguel
AU - Sá, Joaquim
AU - Oliveira, Guiomar
AU - Sá, Maria João
AU - Temudo, Teresa
AU - Sousa, Susana
AU - Marques, Carla
AU - Lopes, Sofia
AU - Gomes, Catarina
AU - Barros, Gisela
AU - Jorge, Arminda
AU - Rocha, Felisbela
AU - Martins, Cecília
AU - Mesquita, Sandra
AU - Loureiro, Susana
AU - Cardoso, Elisa Maria
AU - Cálix, Maria José
AU - Dias, Andreia
AU - Martins, Cristina
AU - Mota, C. u R.
AU - Antunes, Diana
AU - Dupont, Juliette
AU - Figueiredo, Sara
AU - Figueiroa, S. nia
AU - Gama-de-Sousa, Susana
AU - Cruz, Sara
AU - Sampaio, Adriana
AU - Eijk, Paul
AU - Weiss, Marjan M.
AU - Ylstra, Bauke
AU - Rendeiro, Paula
AU - Tavares, Purificação
AU - Reis-Lima, Margarida
AU - Pinto-Basto, Jorge
AU - Fortuna, Ana Maria
AU - Maciel, Patrícia
PY - 2019/7/5
Y1 - 2019/7/5
N2 - 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.
AB - 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.
KW - CNVs
KW - CUL4B overexpression
KW - Genotype-phenotype correlation
KW - Neurodevelopment
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85069268380&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31277718
U2 - https://doi.org/10.1186/s13023-019-1135-0
DO - https://doi.org/10.1186/s13023-019-1135-0
M3 - Article
C2 - 31277718
SN - 1750-1172
VL - 14
SP - 164
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 164
ER -