Idiopathic learning disability and genome imbalance

Abstract

Learning disability (LD) is a very common, lifelong and disabling condition, affecting about 3% of the population. Despite this, it is only over the past 10–15 years that major progress has been made towards understanding the origins of LD. In particular, genetics driven advances in technology have led to the unequivocal demonstration of the importance of genome imbalance in the aetiology of idiopathic LD (ILD). In this review we provide an overview of these advances, discussing technologies such as multi-telomere FISH and array CGH that have already emerged as well as new approaches that show diagnostic potential for the future. The advances to date have highlighted new considerations such as copy number polymorphisms (CNPs) that can complicate the interpretation of genome imbalance and its relevance to ILD. More importantly though, they have provided a remarkable ∼15–20% improvement in diagnostic capability as well as facilitating genotype/phenotype correlations and providing new avenues for the identification and understanding of genes involved in neurocognitive function.

Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects

“…This has led to improved diagnostic capability and, by providing a diagnosis, improving the welfare of patients and their families. 5 Clinical assessment of children with LD typically involves examination by a pediatrician followed by appropriate biochemical and hematological tests as well as chromosomal tests and other molecular genetic tests. Existing cytogenetic tests involve a karyotype analysis followed by fluorescent in situ hybridization or multiplex ligation-dependent probe amplification, which can both identify submicroscopic chromosomal deletions and even single gene deletions located on specific chromosomes.…”

Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis

“…Many similar studies have been published since (reviewed by Koolen et al ,3 Veltman,28 and Knight and Regan29. When taking all studies together, two main conclusions can be drawn: (1) in addition to submicroscopic subtelomeric chromosome imbalances, rare, de novo, submicroscopic interstitial chromosome imbalances or CNVs are responsible for a considerable proportion of cases with MR varying between 5–20%, depending on the clinical pre-selection of the individuals; and (2) these rare de novo CNVs occur all over the genome.…”

Recent Patents on Molecular Cytogenetics

“…microdeletion syndromes or a number of syndromes caused by cytogenetically visible structural chromosome abnormalities) [11] and subtelomeric chromosomal rearrangements, a major cause of mental retardation affecting about 3-7% of mentally retarded individuals [22]. Furthermore, gene-specific probes are widely used for studying known structural chromosome imbalances in malignant cells being extremely valuable for cancer diagnosis and prognosis [6,8,13].…”

“…The latter is used for one hybridization reaction, but, due to exceedingly sophisticated analysis, it is preferred to subdivide the set, i.e. two hybridization reactions with a probe set for subtelomeric regions of 12 chromosomes [22,[28][29][30][31][32][33][34][35][36][37]. The possibilities of conceiving assays for studying these chromosome abnormalities is, in part, advanced by a technology allowing different kinds of hybridization reaction combinations [28].…”