Lipodystrophy and Heritable Pulmonary Arterial Hypertension via the CAV1 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 3 CGL is caused by recessive pathogenic variants in the CAV1 gene (Kim et al. 2008). Other clinical features of Type 3 CGL include preserved mechanical and bone marrow adipose tissue, short stature, functional megaoesophagus, and hypocalcaemia due to vitamin D resistance.

In addition, heterozygous truncating CAV1 variants have been reported to cause partial lipodystrophy, neonatal onset lipodystrophy syndrome and a heritable form of pulmonary arterial hypertension (Cao et al. 2008; Garg et al. 2015; Austin et al. 2012). Of note, pulmonary arterial hypertension (PAH) is a life-threatening condition that progresses to right ventricular failure and death within 5 years of diagnosis in the majority of patients.

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 CAV1 gene (three coding exons) encodes caveolin 1, which is a major component of caveolae. So far, documented genetic defects of CAV1 include missense and truncating pathogenic variants. Only one nonsense variant has been reported to cause CGL. Large deletions and duplications have not been reported (Human Gene Mutation Database).

Detection rate of pathogenic variants in the CAV1 gene in a large cohort of patients with different relevant conditions is unknown in the literature because only limited cases have been reported in individual studies (Human Gene Mutation Database). Analytical sensitivity should be high as all reported pathogenic variants are expected to be detected by sequencing.

This test provides full coverage of all coding exons of the CAV1 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).