Submission Details

Human pathogenic variants in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene, which encodes a protein called seipin, were first reported in association with congenital generalized lipodystrophy 2 (CGL2) in 2001 (Magre et al, PMID:11479539). We have curated the inheritance pattern for BSCL2- related lipodystrophy as autosomal recessive mode of inheritance because, a recessive mode of inheritance has consistently been reported (PMIDs: Jin et al, 18057387, Costa-Riquetto et al, 34033296)

Bi-allelic loss-of-function variants, including nonsense, splice site, frame shift and small deletions in the BSCL2 gene have been reported in individuals with near- complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis, early onset of diabetes, often mild intellectual disability, and in very rare cases, inherited neurological involvement (Celia’s encephalopathy/progressive encephalopathy [PELD], which can also be found in the absence of CGL and is usually caused by variants causing loss of exon 7) (PMIDs: 33916074, 34033296, 29478747, 27144933). Heterozygosity for certain BSCL2 variants believed to cause misfolding of seipin has been implicated in autosomal dominant neurological disorders including Silver spastic paraplegia and distal hereditary motor neuropathy, which do not appear to affect fat metabolism or distribution (PMID:16427281,14981520,18612770).

At least 30 pathogenic variants (primarily frameshift, nonsense or splice site) in the BSCL2 gene have been reported in humans with CGL2. Variants in this gene have been curated in at least 7 probands in 6 publications (PMIDs: 23430896, 18057387, 35351089, 30266686, 30864635, 23659685), with cases presenting as CGL2. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene-disease relationship is supported by multiple knockout mouse models that exhibit a similar phenotype and cellular studies on its role in lipid droplet formation (PMID:23989774,18458148,23680914,22269949). Total points for the experimental evidence are 5. The total score for genetic and experimental evidence together are 17.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism, and phenotype for variants causing congenital generalized lipodystrophy vs. those causing primary neurological conditions. Therefore, we curated BSCL2 as a lumped curation for autosomal recessive congenital generalized lipodystrophy (OMIM: 269700) and progressive encephalopathy with or without lipodystrophy (OMIM 615924). Autosomal dominant neurological conditions including Silver spastic paraplegia syndrome (OMIM: 270685) and distal hereditary motor neuropathy (OMIM: 619112) will be curated separately in split curations.

In summary, BSCL2 is definitively associated with autosomal recessive congenital generalized lipodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

This classification was approved by the ClinGen Monogenic Diabetes GCEP on November 13, 2024 (SOP Version 11).