ESPE Abstracts (2014) 82 FC8.6

A Novel Missense Variant in the Insulin Receptor Gene in Three Unrelated Irish Families with Severe Insulin Resistance Syndrome: Evidence for an Irish Founder Effect

M Mavinkurvea, S O’Connellb, D Codyc, I Isaacd, J Harrisd, R K Sempled & C Mc Donnelle

aChildren’s University Hospital, Temple Street, Dublin, Ireland; bDepartment of Paediatrics and Child Health, Cork University Hospital, Cork, Ireland; cOur Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; dWellcome Trust MRC Institute of Metabolic Science, University of Camridge, Cambridge, UK; eNational Children’s Hospital, AMNCH, Tallaght, Dublin, Ireland

Background: Genetic defects in the insulin receptor (INSR) are rare. Precise prevalence is unknown and significant clinical heterogeneity exists. Over 120 allelic variants have been described to date, spread throughout the receptor, and few geographical founder effects have been described. In this case series we identify a novel missense mutation in the tyrosine kinase domain of the INSR in three independently ascertained Irish families.

Objective and Hypotheses: We aimed to characterise the three affected pedigrees in terms of biochemistry, phenotype and genotype.

Method: Clinical assessment, biochemical profiling and DNA haplotype analysis was performed on the three probands. A detailed family tree was constructed for each index case tracing back over three to four generations reviewing family structure, medical history, features consistent with insulin resistance and migration history.

Results: Two unrelated female and one male proband were identified following referral from three clinical services. Median age at presentation was 11.4 years (range 10.5–12.3). All were term births with weights in the low normal range. At presentation, all three had acanthosis nigricans and BMIs >91st centile (range 23.7–32.5 kg/m2). Fasting blood glucose levels were normal but one child had impaired glucose tolerance. Fasting insulin levels were grossly elevated (range 338–5250 pmol/l) confirming biochemical insulin resistance. All three probands and a parent of each were heterozygous for the novel p.Met1153Lys mutation in the INSR, with a shared haplotype at that locus. While all three unrelated families appeared geographically distinct, we have traced their ancestry to a region in South Central Ireland.

Conclusion: This previously unpublished missense mutation of the INSR gene appears unique to the Irish setting. The shared haplotype provides strong evidence of an Irish founder effect supported by the close geographical proximity of the ancestry of each family. Biochemical and genetic testing of extended family members is in progress.

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