ArticlesSubtle chromosomal rearrangements in children with unexplained mental retardation
Introduction
There are few clinically important disorders as common as mental retardation for which the pathogenesis is so poorly understood. Mental retardation affects about 3% of the population,1, 2 yet a diagnosis is obtained in only about a third of cases. Our poor understanding of its origins hampers the provision of effective treatment and preventive regimens, and remains a major challenge for medical practice.
The causes of mental retardation vary with the severity of the disorder: moderate to severe cases (defined as an IQ score <50) are much more likely to be due to a single pathological cause than are mild cases (IQ score 50–70), which are thought to be multifactorial in origin. Chromosomal and genetic disorders account for 30–40% of cases of moderate to severe mental retardation, environmental factors explain a further 10–30%, and the cause is unknown in about 40% of cases.3, 4, 5, 6 Genetic and environmental causes explain, in roughly equal proportion, about 30% of mild mental retardation; the cause is not known in the remaining 70% of cases.7, 8, 9, 10
There is some evidence that small chromosomal rearrangements involving the terminal bands of chromosomes (subtelomeric regions) are an important unrecognised cause of mental retardation. Case reports have shown cytogenetically invisible subtelomeric rearrangements in mental retardation;11, 12, 13, 14 we carried out a pilot study of the frequency of such rearrangements in children with unexplained mental retardation. Once the low sensitivity and specificity of the test had been taken into account, we estimated that the prevalence of small subtelomeric rearrangements could be as high as 6%, but the 95% CI of our prevalence estimate was large (1–18%).15
The results of the pilot study strengthened our hypothesis that subtelomeric rearrangements are an important cause of mental retardation; however, the findings were inconclusive owing to the low sensitivity of the test and the small sample size. To address these issues, we first developed a new assay, based on fluorescence insitu hybridisation (FISH), that had a sensitivity and specificity of almost 100%.16, 17 We now report a larger study to establish the prevalence of subtelomeric rearrangements in children with unexplained mental retardation, and to assess whether such chromosomal abnormalities have a role in the pathogenesis of this disorder. We also aimed to find out whether, when mental retardation is categorised by severity, the prevalence is the same across all groups, and whether rearrangements are more likely to arise de novo or to be inherited.
Section snippets
Sample selection
374 children (including young adults) with unexplained mental retardation were recruited from nine of 23 clinical genetics centres, and from two community learning disability teams in the UK. All cases with developmental delay or mental retardation, normal routine G-banded karyotype at a 550 band level, and no known cause were studied.
92 families in which at least one child had mild (n=78) or moderate (n=14) mental retardation were contacted through a population-based register of all children
Prevalence of chromosomal abnormalities
We analysed 284 children with moderate to severe retardation, and 182 children with mild retardation. The children enrolled from genetics clinics had moderate to severe mental retardation and minor congenital anomalies. 15% of the special educational needs group had moderate to severe mental retardation, and 21% had minor congenital anomalies. The group with mild mental retardation included 78 children from the special educational needs sample, and 58 children with mild mental retardation and
Discussion
Our results show that subtle chromosomal rearrangements are common in children with mental retardation, that the rearrangements cause the children's disabilities, and that half of the rearrangements are familial. These findings are important for advancing our understanding of the pathogenesis of mental retardation, and for the clinical management of affected children.
The frequency of subtle chromosomal abnormalities among children referred for investigation of unexplained moderate to severe
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