Familial Partial Lipodystrophy (FPLD) Panel

Familial partial lipodystrophies (FPLD) are a group of heterogeneous disorders characterized by selective loss of adipose tissue (Akinci et al. 2018. PubMed ID: 30406415). Subcutaneous fat loss is predominantly observed in the upper extremities, lower extremities, as well as the gluteal and pelvic regions (Ajluni et al. 2017. PubMed ID: 28199729; Lightbourne and Brown. 2017. PubMed ID: 28476236). The exact patterning and regional loss of adipose tissue is highly variable. Adipose tissue sparing and even accumulation may also be observed in the neck, trunk and abdomen of some affected individuals (Ajluni et al. 2017. PubMed ID: 28199729). Onset typically occurs anytime from late childhood through to adulthood. The exact prevalence of FPLD is unknown, but is estimated at approximately 3 cases per million individuals (Chiquette et al. 2017. PubMed ID: 29066925).

At least six main subtypes of FPLD have been described and are associated with pathogenic variation in the CIDEC, LIPE, LMNA, PLIN1, and PPARG genes (Jeru et al. 2017. PubMed ID: 27485410; Lightbourne and Brown. 2017. PubMed ID: 28476236). Several additional genes are also reported to be associated with partial lipodystrophy, although this may be a clinical feature of a broader syndrome (ADRA2A, AKT2, CAV1, LMNB2, POLD1, PSMA3, PSMB4, PSMB8, PSMB9, TBC1D4, and ZMPSTE24). Clinical features may include partial lipodystrophy, a muscular appearance, non-alcoholic steatohepatitis, hypertriglyceridemia, insulin-resistant diabetes mellitus, proteinuria, microalbuminuria, hypertension, peripheral neuropathy, muscular dystrophy, myalgia, gallbladder disease, pancreatitis, as well as cardiovascular disease (Ajluni et al. 2017. PubMed ID: 28199729). Female patients may also exhibit mild hirsutism, irregular menstrual periods, and polycystic ovarian disease (Garg. 2004. PubMed ID: 10843151). Medical management may include surveillance, psychological support, restriction of total fat intake, caloric restriction, increased physical activity, therapy for diabetes mellitus and hyperlipidemia, and possibly cosmetic surgery (Akinci et al. 2018. PubMed ID: 30370487). Genetic testing may aide in establishing a differential diagnosis, predicting the course of disease, and may assist reproductive planning.

Pathogenic variants in one or more of these genes included as part of this panel are reported to be associated with additional phenotypes including (but not limited to) congenital generalized lipodystropy, progeroid syndromes, insulin resistance, severe obesity, skeletal dysplasia, neuropathy, muscular dystrophy, dermopathy, colorectal cancer, epilepsy susceptibility, and pulmonary hypertension.

FPLD and associated syndromes may be inherited in an autosomal dominant (ADRA2A, AKT2, CAV1, LMNA, LMNB2, PSMA3, PLIN1, POLD1, PPARG, TBC1D4) or recessive manner (CIDEC, LIPE, PSMB4, PSMB8, PSMB9, ZMPSTE24). Pathogenic variants may be inherited from a carrier parent, an affected parent, or arise de novo (Garg et al. 2016. PubMed ID: 27376152; Lightbourne and Brown. 2017. PubMed ID: 28476236). FPLD is associated with small deletions, nonsense, splice site, frameshift, missense, and regulatory pathogenic variants. To date, structural variants have been reported only in isolated and familial cases of a related disorder, congenital generalized lipodystrophy (Agarwal et al. 2002. PubMed ID: 11967537; Purizaca-Rosillo et al. 2017. PubMed ID: 27868354). Pathogenic variants in the LMNA and PPARG genes are estimated to account for more than 50% of all cases of FPLD (Jeru et al. 2017. PubMed ID: 27485410). More than 80% of pathogenic variants associated with FPLD in the LMNA gene localize to a hotspot at arginine residue 482 (Jeru et al. 2017. PubMed ID: 27485410).

Although the function of some of the genes included in this panel are yet to be fully elucidated, several are known to be involved in adipogenesis, lipolysis, and biogenesis of caveolae (Holm et al. 1988. PubMed ID: 3420405; Peng et al. 2003. PubMed ID: 12782654; Evans et al. 2004. PubMed ID: 15057233; Capanni et al. 2005. PubMed ID: 15843404; Puri et al. 2007. PubMed ID: 17884815; Bosch et al. 2011. PubMed ID: 21497090).

See individual gene summaries for more information about the molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of FPLD, the clinical sensitivity of this specific grouping of genes is difficult to estimate. However, pathogenic variants in the LMNA and PPARG genes are estimated to account for more than 50% of all cases of FPLD (Jeru et al. 2017. PubMed ID: 27485410). Outside of these two genes, pathogenic variants explain only a small subset of FPLD cases.

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

This panel provides 100% coverage of all coding exons of the genes 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 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).