Study methodology. Using genetic epidemiology to study Rett syndrome: the design of a case–control study

Abstract

Rett syndrome is a neurological disorder that is seen almost exclusively in females. Although generally considered to have a genetic basis, the underlying mechanism remains obscure. One favoured hypothesis is that the syndrome is an X-linked dominant disorder, lethal or non-expressed in males. Genealogical research has also suggested that the mode of transmission in Rett syndrome may involve a premutation which over several generations is converted to a full mutation. Geographical clustering has been reported, and it has also been proposed that Rett syndrome is a clinically variable condition and that other neurological disorders may be occurring more commonly in families with Rett syndrome. Other studies have found an apparent increase in intellectual disability and seizures in the extended families of girls with Rett syndrome. The science of genetic epidemiology can be used to identify familial aggregation, which is the clustering of a disorder within a family. We have used a case-control study design to investigate both fetal wastage and familial aggregation of other disorders in families of girls with Rett syndrome. The Australian Rett Syndrome Database provided the source of cases, and control probands were girls of a similar age with normal development. This paper describes the methodology for a case-control study of this rare condition using pedigree data and discusses issues in the collection and evaluation of such data. The use of a control population is an important feature. Both the strengths and the shortcomings of our design are identified, and recommendations are made for future research.

The epidemiology of mental retardation: Challenges and opportunities in the new millennium

“…In such studies it will be important to take into account the confounding effects of age and other nongenetic influences on the phenotype. Population-based registers such as that in Australia for Rett syndrome provide an excellent source of cases for such studies [Leonard et al, 2000a] but unfortunately such registers rarely exist for other syndromes. Cases tend to be selected for study based only on clinic referral patterns and may not be representative of the underlying population of affected subjects.…”

Impacts of national surveillance for uncommon conditions in childhood

“…The APSU surveillance study facilitated research in molecular genetics, including studies of specific genotype–phenotype correlations. Genetic testing now allows early confirmation of the diagnosis in subgroups of children, and in turn facilitates early access to specialised multidisciplinary care 31,32 …”

Family data in Rett syndrome: Association with other genetic disorders

“…Reliance on parental report for classification of disorders may provide an additional source of error in addition to those previously discussed. 5 Although occasionally possible, in general our study did not have the capacity to follow up individual diagnoses and hence classify them more definitively.…”

“…Data collection methods have previously been described and study strengths and weaknesses discussed. 5 Because major clinical centres in each state were not fully involved in our Australia‐wide epidemiological project, access to patient records was only possible for the small proportion of cases registered with the Disability Services Commission in Western Australia. In brief, pedigrees were collected from 110 case families, representing 79% of cases ascertained at that time by the Australian Rett Syndrome Study.…”