Selection against mutant alleles in blood leukocytes is a consistent feature in Incontinentia Pigmenti type 2

Incontinentia Pigmenti 2 (IP2) is an X-linked dominant disorder with male lethality, Affected females display a characteristic skin eruption that evolves through four classic stages, frequently accompanied by dental and retinal abnormalities, Non-random (skewed) X-inactivation in peripheral blood leukocytes and in fibroblasts has been observed in females with IP2; however, sample sizes have been small and methods of analysis varied, We have examined X-inactivation in a large group of multigenerational IP2 families, in smaller families, and in isolated cases, Ninety-eight percent of affected females in multigenerational IP2 pedigrees show completely skewed patterns of X-inactivation, while only similar to 10% of a normal control population is skewed, Results both in small families and in new mutation cases with subsequent segregation consistent with Xq28 linkage are similar, Isolated cases show a lower percentage (85%) of skewed affected individuals; this difference may be due to inaccurate clinical ascertainment, The parent of origin of new mutations could be determined in 15 families; paternal new mutations were twice as common as maternal, Fibroblast subclones from a biopsy at the boundary of a skin lesion in a newborn IP2 patient were isolated, and clones with either one or the other X active were identified, demonstrating that cells with the active disease-bearing X chromosome are still present in stage I skin lesions.