Type 6 Familial Partial Lipodystrophy via the LIPE Gene

Pathogenic variants in the LIPE gene are associated with type 6 familial partial lipodystrophy (FPLD), a rare disorder characterized by abnormal subcutaneous fat distribution and metabolic and endocrine dysfunction. This disorder is also referred to as hormone-sensitive lipase deficiency. Subcutaneous fat loss is predominantly observed in the lower extremities. Abnormal subcutaneous fat accumulation may be observed in the neck, clavicular regions, axillae, back, triceps, and external female genitalia (Albert. 2014. PubMed ID: 24848981; Farhan et al. 2014. PubMed ID: 25475467; Carboni et al. 2014. PubMed: 24375490; Zolotov et al. 2017. PubMed ID: 27862896). Visceral fat accumulation may also be observed. The exact patterning of subcutaneous fat may vary between individuals. Metabolic and endocrine features may include type 2 diabetes mellitus, dyslipidemia, hepatic steatosis, insulin resistance, and increased serum creatine kinase levels. Some individuals may develop myopathy or mild skeletal muscle abnormalities. Endocrine and metabolic anomalies may be evident in early adulthood. Partial lipodystrophy and myopathy may become evident during adulthood. It should be noted that a limited number of cases have been reported and that some features may be variable.

The exact prevalence of FPLD is unknown, but is estimated at approximately 3 cases per million individuals (Chiquette et al. 2017. PubMed ID: 29066925). FPLD is associated with pathogenic variants in several genes. Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the LIPE gene are associated with autosomal recessive type 6 FPLD. A homozygous nonsense variant and 2 homozygous frameshift variants have been reported in 9 individuals with type 6 FLD from 3 unrelated consanguineous families of Isralei-Arab, Italian and Old Order Amish descent (Albert. 2014. PubMed ID: 24848981; Farhan et al. 2014. PubMed ID: 25475467; Carboni et al. 2014. PubMed: 24375490; Zolotov et al. 2017. PubMed ID: 27862896). Of note, heterozygous individuals may be at increased risk of developing type 2 diabetes mellitus (Albert. 2014. PubMed ID: 24848981). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The LIPE gene encodes hormone sensitive lipase (HSL), a  ubiquitously expressed enzyme that has multiple roles in lipid metabolism including catalyzing hormone-stimulated lipolysis in adipocytes, steroidogenesis, and spermatogenesis (Haemmerle et al. 2003. PubMed ID: 12840660; Yeaman. 2004. PubMed ID: 14725507). LIPE has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). Experimental studies of adipose tissue from individuals with type 6 FPLD demonstrate decreased LIPE mRNA, absence of HSL protein, impaired lipolysis, insulin resistance, and inflammation (Albert et al. 2014. PubMed ID: 24848981). HSL-deficient mice are not obese, but with age display phenotypic similarities to partial lipodystropy (Osuga et al. 2000. PubMed ID: 10639158). In addition, male HSL-deficient mice are sterile due to oligospermia.

The clinical sensitivity of type 6 FPLD is difficult to estimate, as to date, a limited number of cases have been described in the literature (Albert. 2014. PubMed ID: 24848981; Farhan et al. 2014. PubMed ID: 25475467; Carboni et al. 2014. PubMed: 24375490; Zolotov et al. 2017. PubMed ID: 27862896). Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the LIPE gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).

This test is performed using Next-Generation sequencing on our exome backbone. There is the option to reflex to whole exome sequencing (PGxome).