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Orphanet J Rare Dis. 2019 Jul 5;14(1):164. doi: 10.1186/s13023-019-1135-0.

Genomic imbalances defining novel intellectual disability associated loci.

Author information

1
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal.
2
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
3
CGC Genetics, Porto, Portugal.
4
Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
5
Center for Medical Genetics Dr. Jacinto Magalhães, Porto Hospital Center, Praça Pedro Nunes, Porto, Portugal.
6
Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
7
The Mindich Child Health & Development Institute and the Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
The Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10
Centro de Genética Preditiva e Preventiva - CGPP, Instituto de Biologia Molecular e Celular - IBMC, Universidade do Porto, Porto, Portugal.
11
Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Porto, Portugal.
12
Unidade de Neurodesenvolvimento e Autismo do Serviço do Centro de Desenvolvimento da Criança and Centro de Investigação e Formação Clínica, Pediatric Hospital, Centro Hospitalar e Universitário de Coimbra, 3041-80, Coimbra, Portugal.
13
University Clinic of Pediatrics and Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
14
Medical Genetics Unit, Hospital de Braga, Braga, Portugal.
15
Department of Medical Genetics, Hospital de Faro, Faro, Portugal.
16
Pediatric Neurology Department, Centro Materno-Infantil Centro Hospitalar do Porto, Porto, Portugal.
17
Development Unit, Pediatrics Service, Hospital Centre of Cova da Beira, Covilhã, Portugal.
18
CICS - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
19
Department of Pediatrics, Médio Ave Hospital Center, Vila Nova de Famalicão, Portugal.
20
Department of Pediatrics, Hospital S. Teotónio, Tondela/Viseu Hospital Center, Viseu, Portugal.
21
Neuropaediatric Unit - Garcia de Orta Hospital, Almada, Portugal.
22
Pediatric and Neonatal Intensive Care, Department of Pediatrics, Porto Hospital Center, Porto, Portugal.
23
Department of Genetics, Hospital D. Estefânia, Lisboa-Norte Hospital Center, Lisbon, Portugal.
24
Genetics Service, Paediatric Department, University Hospital Santa Maria, Lisbon, Portugal.
25
Department of Pediatrics, Médio Ave Hospital Center, Santo Tirso, Portugal.
26
Division of Pediatric Neurology, Department of Child and Adolescent, Centro Hospitalar do Porto e Hospital de Santo António, Porto, Portugal.
27
Neuropsychophysiology Lab, CIPsi, School of Psychology, University of Minho, Braga, Portugal.
28
Department of Pathology, VU University Medical Center, Amsterdam, 1007, MB, The Netherlands.
29
Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1007, MB, The Netherlands.
30
GDPN- SYNLAB, Porto, Portugal.
31
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal. pmaciel@med.uminho.pt.
32
ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. pmaciel@med.uminho.pt.

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.

KEYWORDS:

CNVs; CUL4B overexpression; Genotype-phenotype correlation; Neurodevelopment

PMID:
31277718
DOI:
10.1186/s13023-019-1135-0
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