Next-Generation Sequencing-Based Genetic Testing For Familial Partial Lipodystrophy

ABSTRACT Objective: Familial partial lipodystrophy (FPL) of the Dunnigan type (FPLD) is an autosomal dominant condition characterized by fat loss in the limbs and trunk, fat accumulation in the head and neck, and early onset diabetes mellitus. Here we describe the establishment and utilization of next-generation sequencing (NGS)-based genetic testing for FPLD. Methods: We describe NGS-based mutational analysis of the lamin A/C (LMNA) gene, followed by confirmation through Sanger sequencing. Results: We report a patient and her mother with accumulation of fat in the neck and face and loss of fat in the limbs and trunk typical of FPLD2, with young onset diabetes mellitus without ketoacidosis. Both subjects had elevated homeostasis model assessment estimated insulin resistance (HOMA-IR) values and serum triglyceride levels, indicating insulin resistance. Dual energy X-ray absorptiometry confirmed typical fat redistribution. NGS-based mutational analysis of the LMNA gene in these patients revealed a hot spot missense mutation (c.1444C>T, p.Arg482Trp) that was further confirmed by Sanger sequencing. Conclusion: A high index of clinical suspicion is essential to make an accurate clinical diagnosis in subjects with diabetes at an early age. FPLD should be considered in the differential diagnosis of monogenic diabetes with lipodystrophy. Ion torrent NGS offers flexibility and a multiplexing option that provides a robust and inexpensive platform for screening single-gene disorders. Abbreviations: FPL familial partial lipodystrophy FPLD familial partial lipodystrophy of the Dunnigan type NGS next-generation sequencing