Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is characterized by extreme floppiness at birth, impaired sexual development, short stature, severe over-eating, characteristic physical features and learning disabilities (LD). Impaired social cognition, literal mindedness and cognitive inflexibility are also present. The syndrome has two main genetic subtypes that both result in the failure of expression of maternally imprinted genes on chromosome 15 at the locus q11-13.

Through multiple sources, we attempted to identify all people with PWS living in one health region in the UK. Additional people with PWS identified in other regions were also recruited to augment the study sample. A comparison group of people with LD as a result of aetiologies other than PWS was also identified. All people from these three groups, over age three, who gave their consent, were assessed using tests of ability and attainment. In addition, their main carers were interviewed using a semistructured interview. Blood samples for genetic diagnosis were obtained from all consenting participants.

The IQ distribution of the population sample was approximately normal with a mean IQ 40 points below that of the general population. There were systematic differences between the two main genetic subtypes. Those with disomies differed in cognitive profiles from both those with deletions and the comparison LD group (the latter two groups were very similar) in terms of better verbal abilities and impaired coding ability. Some people with PWS deletions had strong visuospatial skills.

We propose that the normal distribution of IQ, shifted downwards relative to that of the general population, is the result of a global effect on IQ of the PWS gene(s), and that the different cognitive profile seen in those with chromosome 15 maternal disomies is a specific effect of a gene, or genes, on chromosome 15 which is differentially either expressed or not expressed in those with disomies relative to those with deletions. One hypothesis is that these subtle cognitive differences are a manifestation of the genetic influences of gender-specific imprinted genes on cerebral lateralization. This requires further investigation.