Congenital Generalized Lipodystrophy (CGL) via the CAVIN1 (PTRF) 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 4 CGL is caused by defects in the CAVIN1 (PTRF) gene (Hayashi et al. 2009). Other clinical features of Type 4 CGL include preserved mechanical and bone marrow adipose tissue, cardiomyopathy, ventricular arrhythmia, extended QT interval and sudden death, osteopenia, distal metaphyseal deformation with joint stiffness, atlanto-axial instability, congenital pyloric stenosis, and congenital myopathy.

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 CAVIN1. 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 CAVIN1 gene (two coding exons) encodes polymerase I and transcript release factor, which is an essential factor in the biogenesis of caveolae. So far, documented genetic defects of CAVIN1 include missense and truncating pathogenic variants. Large deletions and duplications have not been reported (Human Gene Mutation Database).

In a study of Japanese patients, pathogenic CAVIN1 variants were found in all five nonconsanguineous patients whose muscle showed caveolin-3 deficiency, but no CAV3 pathogenic variant among a total of 2,745 muscular dystrophy patients (Hayashi et al. 2009).

This test provides full coverage of all coding exons of the CAVIN1 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).