Abstract

In this study, we analysed the mutation spectrum in subjects with suspected lipodystrophy using a targeted Next-generation sequencing (NGS) approach. Subjects with suspected lipodystrophy were for screened six genes (AGPAT2, BSCL2, LMNA, PPARG, ZMPSTE24, INSR) and the variants identified were confirmed through Sanger sequencing. The clinical and biochemical parameters were compared among the mutation positive and negative subjects. We identified eight individuals with pathogenic or likely pathogenic mutations, including both homozygous and heterozygous variants. Homozygous variants included  AGPAT2(NM_006412.4):c.493-2A>G, AGPAT2(NM_006412.4):c.254_258dup, and BSCL2(NM_001122955.4):c.570del, while heterozygous variants encompassed LMNA(NM_170707.4):c.1444C>T, LMNA(NM_170707.4):c.1456A>G, LMNA(NM_170707.4):c.1445G>A, and PPARG(NM_015869.5):c.949T>C mutations. In this cohort, three subjects were diagnosed with congenital generalized lipodystrophy, while the remaining five had familial partial lipodystrophy. Majority (7/8) of the patients with lipodystrophy had hepatic involvement. Notably, more than half of the subjects (5/8) achieved optimal glycemic control through insulin sensitizers (PPARγ agonist and Metformin). Interestingly, even with a limited gene panel test, mutation-positive individuals exhibited a higher prevalence of typical clinical features and biochemical characteristics associated with lipodystrophy compared to their mutation-negative counterparts. In subjects with lipodystrophy, targeted NGS based screening may establish a genetic diagnosis and aid in family screening and genetic counselling. Knowing the clinical and biochemical features typical to lipodystrophy may help in diagnosis especially in resource limited setting.