A review of: Knight SJL, Regan R, Nicod A, et al. 1999 Subtle Chromosomal Rearrangements in Children with Unexplained Mental Retardation. Lancet 354:1676–1681.

Mental retardation (MR) is reported to affect approximately 3% of the population, but in only 30% of cases can a specific diagnosis be identified. The greater the degree of MR (moderate-severe as compared to mild), the more likely a genetic, chromosomal, or environmental disorder will be discovered. In an earlier pilot study, using a fluorescence in-situ hybridization (FISH) test, the authors reported that subtle subtelomeric rearrangements might be responsible for unexplained MR in a significant number of children (1). The present report provides additional information on a larger cohort of subjects with unknown causes of MR (284 moderate MR, 182 mild MR), selected from genetic and learning disability clinics in the United Kingdom who previously had normal G-banded karyotypes, as well as 75 controls (2). Compared to 0% in controls, the prevalence of subtelomeric chromosomal rearrangements was 7.4% in children with moderate MR (95% CI = 4.4–10.4) and 0.5% for those children with mild MR (95% CI = 0–1.6). Each child (n = 22) with a chromosomal rearrangement had evidence of an abnormality on physical examination, ranging from a minor anomaly in approximately 25% (e.g. mild facial dysmorphism) to 75% with significant abnormalities (e.g. central nervous system, skeletal and cardiac anomalies). The parents of the affected children were also studied. Approximately 50% of the examined parents were found to carry a balanced chromosomal rearrangement. In families with a child found to have a chromosomal rearrangement causing MR, it is now possible to investigate the extended family for the rearrangement and provide family counselling for those carrying a balanced rearrangement.

Until studies reporting the association between chromosomal rearrangements were reported a few years ago (3), it was commonly believed that following the exclusion of major chromosomal abnormalities utilizing conventional techniques, as well as specific metabolic and neuroimaging studies, the most common causes of moderate-severe MR was on the basis of environmental or perinatal factors. Data from this study suggest that subtle chromosomal rearrangements may be second only to Down syndrome as a cause of moderate MR, and also provide an explanation why different phenotypes may occur in the same family.

The advantage of the FISH test utilized in the current study is that it scans all the chromosome ends of the genome of the subject and provides more accurate information than conventional high-resolution techniques. What is not known is the frequency of these subtelomeric rearrangements in the normal population and the clinical relevance of every subtelomeric rearrangement that may be detected. The study of 75 controls in the study by Knight et al. is unfortunately too small to answer these important questions, however, many investigators would not support a population screening study to determine the prevalence of these chromosomal rearrangements because of ethical and practical considerations.

There remains some uncertainty as to who should be screened with subtelomeric probes. The authors suggest that all children with unexplained moderate to severe MR should be tested. In view of these exciting findings, many genetic clinics are initiating studies to determine the prevalence of chromosomal rearrangements as a cause of MR within their communities. Many have devised inclusion criteria, which generally consist of a combination of unexplained MR, multiple congenital abnormalities, abnormal growth patterns, and dysmorphic features, to determine which children should be tested. Whatever the ultimate results of these investigations, the current study is a clear demonstration of the enormous progress in the field of cytogenetics, moving in only a few years from the classification of major defects, to the identification of minimal structural chromosomal abnormalities associated with significant morbidity.