Congenital Generalized Lipodystrophy (CGL) via the AGPAT2 Gene

Congenital generalized lipodystrophy (CGL) is a group of heterogeneous autosomal recessive disorders characterized by a near complete loss of adipose tissue from birth and predisposition to metabolic complications later in life including diabetes mellitus, hypertriglyceridaemia and hepatic steatosis (Patni et al. 2015). Four distinct subtypes of CGL have been defined and are caused by defects in four respective genes. Type 1 CGL is caused by defects in the AGPAT2 gene (Agarwal et al. 2002). Other clinical features of Type 1 CGL include preserved mechanical adipose tissue, focal lytic lesions in the long bones after puberty, as well as acromegaloid features with enlarged mandible, hands and feet.

Congenital generalized lipodystrophy (CGL) is inherited in an autosomal recessive manner (Patni et al. 2015). Four distinct subtypes of CGL have been defined and are caused by defects in four respective genes: AGPAT2, BSCL2, CAV1 and PTRF. The encoded proteins of these genes play key roles in phospholipid and triglyceride synthesis, the fusion of lipid droplets, and the biogenesis of caveolae within adipocytes.

The AGPAT2 gene (six coding exons) encodes 1-acyl-sn-glycerol-3-phosphate acyltrans­ferase β, which is involved in triglyceride biosynthesis. So far, documented genetic defects of AGPAT2 include missense and truncating pathogenic variants (Human Gene Mutation Database). A large deletion within the AGPAT2 gene has also been reported (Human Gene Mutation Database).

In a study of 45 unrelated families with congenital generalized lipodystrophy, sequencing for the AGPAT2 and BSCL2 genes found pathogenic variants in AGPAT2 in 26 families and in BSCL2 in 11 families, respectively (Agarwal et al. 2003).

This test provides full coverage of all coding exons of the AGPAT2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).