Diagnostic methods for somatic and germ line mosaicism

(A) Hypothetical pedigree of Segmental neurofibromitosis type 1, and (below) molecular analysis showing somatic mosaicism. The three-generation pedigree illustrates the occurrence of a sporadic mutation (shown in red) in a second-generation male (represented as squares) manifested as a cafe-au-lait skin lesion that is typical of NFI. Although this disorder is typically inherited as an autosomal-dominant trait, none of the offspring of the affected individual show the abnormality. Moreover, molecular analysis reveals a putative deletion (MUT) in the NF1 gene in DNA obtained from the abnormal skin of the affected patient. By contrast, only wild-type (WT) DNA is noted in the other tissues. The combination of the clinical information and the molecular information supports the diagnosis of a somatic mosaic state in the affected patient. (B) Hypothetical pedigree and molecular analysis showing germ-line mosaicism in tuberous sclerosis. Although this disorder is inherited as an autosomal-dominant trait, the pedigree is more consistent with either autosomal-recessive inheritance or germ-line mosaicism for a mutation in one of the tuberous sclerosis genes in one of the parents. DNA analysis reveals that the father's germ cells, but not other tissues, harbour the mutation (MUT). Due to the inaccessibility of female germ cells, the molecular analysis in such instances frequently remains incomplete.