Abstract
BackgroundChromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Its use has revealed the capacity to detect copy number variants (CNVs), as well as regions of homozygosity, that, based on their distribution on chromosomes, indicate uniparental disomy or parental consanguinity that is suggestive of an increased probability of recessive disease.ResultsWe screened 149 Lebanese probands with ID/DD and 99 healthy controls using the Affymetrix Cyto 2.7 M and SNP6.0 arrays. We report all identified CNVs, which we divided into groups.Pathogenic CNVs were identified in 12.1% of the patients. We review the genotype/phenotype correlation in a patient with a 1q44 microdeletion and refine the minimal critical regions responsible for the 10q26 and 16q monosomy syndromes.Several likely causative CNVs were also detected, including new homozygous microdeletions (9p23p24.1, 10q25.2, and 8p23.1) in 3 patients born to consanguineous parents, involving potential candidate genes.However, the clinical interpretation of several other CNVs remains uncertain, including a microdeletion affecting ATRNL1. This CNV of unknown significance was inherited from the patient’s unaffected-mother; therefore, additional ethnically matched controls must be screened to obtain enough evidence for classification of this CNV.ConclusionThis study has provided supporting evidence that whole-genome analysis is a powerful method for uncovering chromosomal imbalances, regardless of consanguinity in the parents of patients and despite the challenge presented by analyzing some CNVs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-015-0130-y) contains supplementary material, which is available to authorized users.
Highlights
Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies
Our findings underscore the implication of clinically relevant copy number variants (CNVs) in ID/DD and emphasize the ability of the technique in detecting regions of homozygosity (ROH) that are highly suggestive of an increased likelihood of rare recessive diseases. In this cohort of 149 Lebanese patients having ID, DD, with or without congenital abnormalities (CA), we found an average of 6 chromosomal imbalances per proband of which 67.8% had previously been reported as benign
All CNVs belonging to group I were of de novo origin, except for one that was inherited from the father of patient P10 [12]
Summary
Chromosomal microarray analysis (CMA) is currently the most widely adopted clinical test for patients with unexplained intellectual disability (ID), developmental delay (DD), and congenital anomalies. Intellectual disability (ID) is defined as a significant limitation in both intellectual function and adaptive behavior that originates before the age of 18 [1]. ID with a genetic origin is more frequently found in patients with an IQ < 50 (50%) than in other patients (15%), with chromosomal aberrations being the most common causes [7,8]. Screening for these imbalances is routinely performed with conventional cytogenetic and molecular tests. The resolution is limited to 5 Mb in standard karyotyping; the detection of imbalances is successful only in less than 4% of patients with ID
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