BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels. METHODS AND RESULTS: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation. CONCLUSIONS: We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease.Progeria experiments were funded by The Progeria Research Foundation grants PRF-2002-CB and PRF-2002-MRD (JFB, WEN, SEC, LBG), and by the Medical Research Council UK grant MR/L019116/1 (DL). Core and general laboratory grants are as follows: Kilguss Research Core of Women & Infants Hospital of Rhode Island through an Institutional Development Award from the NIGMS of the NIH (P30GM114750), intramural funds to the NHGRI (ZIA-HG200305), Cancer Research UK programme grant C6/A18796 and Wellcome Trust (WT092096)
