1) MC1R - proposal to use 300 Children in Focus blood samples, selected by the following criteria:

a) those who have had a pigmentary phenotype recorded at 49 months (hair and eye colour etc)

b) the subset of those children who did not have a congenital melanocytic naevus recorded at 49 months

At Great Ormond Street Hospital we have recruited 110 families to our study into the genetics of congenital melanocytic naevi (CMN). CMN is a developmental neurocutaneous disorder of unknown aetiology in which affected individuals have extensive pigmented lesions covering up to 80% of the body surface and up to 400 lesions. The cutaneous lesions are associated with a range of neurological abnormalities in around 20% of affected children, for which all children are screened in the absence of any identified biomarkers. A small proportion of children develop fatal malignant melanoma, again necessitating blanket screening.

We have identified a high prevalence of melanocortin-1-receptor (MC1R) variants in this cohort (70 - 80%) and have shown a statistically significant association between certain polymorphisms and a more severe clinical phenotype. This is a potentially useful finding in a clinical setting as generally it is those with a more severe phenotype who develop malignant and neurological complications. We cannot however adequately evaluate the relevance of this finding as the existing publications on UK prevalence for MC1R variants is conflicting. Two relatively small studies have found prevalences of 25% and 55% of at least one variant. We have attempted to recruit a case-matched control group using the participant families to identify geographically-, age- and gender-matched children. The return on our recruitment has been very low, and simultaneous problems amplifying DNA from buccal swabs returned by families in the post has shrunk our control group to inadequate numbers.

The use of 300 Children in Focus ALSPAC cases' data and samples for whom a pigmentary phenotype (hair and eye colour) is available and who were not found to have congenital melanocytic naevi will be as a control group to establish the normal prevalence of MC1R polymorphisms in a representative UK population. The figure of 300 was arrived at by sample size calculation. The whole of the MC1R gene will need to be sequenced as there are a large number (greater than 20) common polymorphisms described. DNA will be sequenced by the UCL sequencing service. The prevalence of polymorphisms and pigmentary phenotyping data will then be compared statistically to that of the CMN group to see if MC1R is involved as a predisposing factor for the development of CMN.

2)Endocrine and cancer family history

We have also found that the families in the CMN group appear to have a high prevalence of endocrine disorders and perhaps also of cancer. There are other disorders of pigmentation which have associated endocrine abnormalities (for example McCune-Albright Syndrome) and many which are associated with increased susceptibility to tumours (Neurofibromatosis, Tuberous Sclerosis). It is again biased to collect family history data from a hospital based control population, and although we have done this for our control set the numbers are very small and not statistically useable. ALSPAC data about family history would be very valuable control data for this exploratory arm of this genetics study, enabling us to make decisions about candidate genes and pathways