Generalized, Partial and Atypical Lipodystrophy Panel

Lipodystrophies are a group of heterogeneous disorders characterized by loss of adipose (fat) tissue (Akinci et al. 2018. PubMed ID: 30406415). Lipodystrophy may be genetic or acquired. Broadly, the genetic lipodystrophies are classed as congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPLD), or atypical and/or complex lipodystriophy, which may occur as a feature of progeroid syndromes (Akinci et al. 2018. PubMed ID: 30406415). Clinical features and severity vary depending of the type of lipodystrophy and the underlying genetic cause.

CGL is characterized by a near complete loss of adipose tissue at or soon-after birth and is typically accompanied by severe metabolic dysregulation (Patni and Garg. 2015. PubMed ID: 26239609; Akinci et al. 2018. PubMed ID: 30406415). Clinical features associated with CGL may include generalized lipodytrophy, a muscular appearance, prominent veins, accelerated growth, voracious appetite, umbilical hernias, hepatomegaly, splenomegaly, acanthosis nigricans, advanced bone age, and metabolic complications (insulin resistance, hypertriglyceridaemia, hepatic steatosis) (Patni and Garg. 2015. PubMed ID: 26239609; Akinci et al. 2018. PubMed ID: 30406415). The exact prevalence of CGL is unknown, but is estimated to be approximately 0.2 to 1 cases per million individuals (Chiquette et al. 2017. PubMed ID: 29066925).

FPLD is typically characterized by selective loss of adipose tissue, predominantly 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). Clinical features may also include 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). 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).

Atypical and/or complex lipodystropy may present with progeroid syndromes, cutis laxis, Keppen-Lubinsky syndrome, Ruijs-Aalfs syndrome, SHORT syndrome and CANDLE syndrome (Akinci et al. 2018. PubMed ID: 30406415). Clinical features for these syndromes may include a marfanoid or progeroid appearance, dermatological features, retinal features, and skeletal, cardiovascular and/or neurologic anomalies. Onset may occur at birth, soon-after birth, during childhood, or adolescence.

Medical management for lipodystrophy 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) progeroid syndromes, insulin resistance, severe obesity, skeletal dysplasia, neuropathy, muscular dystrophy, dermopathy, colorectal cancer, epilepsy susceptibility, and pulmonary hypertension.

CGL is primarily inherited in an autosomal recessive manner (AGPAT2, BSCL2, CAV1, CAVIN1), however dominant inheritance is reported for atypical causes of CGL (FBN1, KCNJ6, LMNA, PPARG). FPLD may be inherited in an autosomal dominant (ADRA2A, AKT2, CAV1, LMNA, LMNB2, PLIN1, POLD1, PPARG, PSMA3, TBC1D4) or recessive manner (CIDEC, LIPE, PSMB4, PSMB8, PSMB9, ZMPSTE24). Atypical and/or complex lipodystropies are predominantly inherited in an autosomal recessive manner (BANF1, IGF1R, MFN2, PCYT1A, PIK3R1, SPRTN, WRN), although dominant inheritance is reported for the IGF1R, MFN2, and PSMA3 genes. Pathogenic variants may be inherited from a carrier parent, an affected parent, or arise de novo (Brehm et al. 2015. PubMed ID: 26524591; Lightbourne and Brown. 2017. PubMed ID: 28476236). The lipodystrophies are associated with small deletions, nonsense, splice site, frameshift, missense, and regulatory pathogenic variants. Structural variants, predominantly in the form of gross deletions, have been reported in isolated and familial cases of CGL (Agarwal et al. 2002. PubMed ID: 11967537; Purizaca-Rosillo et al. 2017. PubMed ID: 27868354). Structural variants, predominantly in the form of gross deletions, have also been reported in isolated cases of adult progeria Werner syndrome (Friedrich et al. 2010. PubMed ID: 20443122).

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 phospholipid and triglyceride synthesis, the fusion of lipid droplets, 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; Patni and Garg. 2015. PubMed ID: 26239609).

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

Due to the genetic heterogeneity underlying the lipodystropies, the clinical sensitivity of this specific grouping of genes is difficult to estimate. However, it has been reported that up to 80% of individuals with CGL have an identifiable genetic cause (Akinci et al. 2018. PubMed ID: 30406415). 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. Presently, clinical sensitivity estimates for atypical and/or complex cases of lipodystrophy are unknown.

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

This panel typically provides 99.6% 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).