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.
- Other cardiovascular medicine
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DZB, MFA and JFB contributed equally.
Contributors Each author listed on the manuscript has participated in editing the manuscript, has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript. In addition, DZB and MFA conducted, analysed and interpreted the deep sequencing experiments; JFB and SEC acquired and analysed phenotypic data; WEN acquired and processed all patient samples, and analysed data. PC and TWG performed and interpreted Sanger sequencing and paternity validation studies; SPJ and DL commissioned the sequencing studies that led to the initial identification of genetic mosaicism in the patient. FSC and TWG contributed to study design and data analysis. LBG was responsible for primary study oversight and design, data acquisition, data analysis and interpretation, and primary writing of the manuscript.
Funding 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).
Competing interests None.
Patient consent Obtained.
Ethics approval Rhode Island Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.