Congenital generalized lipodystrophy: identification of novel variants and expansion of clinical spectrum

Congenital generalized lipodystrophy(CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2variants cause CGL type 2 with more severe features. Muscle hypertrophycaused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype–phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2(five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhageand nephrolithiasis in CGL patients. Generalized lipodystrophyand muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cystsand history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype–phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counselingin families at-risk.