Genotype-phenotype correlations of Berardinelli-Seip congenital lipodystrophy and novel candidate genes prediction

Abstract

Background: Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous autosomal recessive disorder characterized by an almost total lack of adipose tissue in the body. Mutations in the AGPAT2, BSCL2, CAV1 and PTRF genes define I-IV subtype of BSLC respectively and clinical data indicate that new causative genes remain to be discovered. Here, we retrieved 341 cases from 60 BSCL-related studies worldwide and aimed to explore genotypephenotype correlations based on mutations of AGPAT2 and BSCL2 genes from 251 cases. We also inferred new candidate genes for BSCL through protein-protein interaction and phenotype-similarity. Results: Analysis results show that BSCL type II with earlier age of onset of diabetes mellitus, higher risk to suffer from premature death and mental retardation, is a more severe disorder than BSCL type I, but BSCL type I patients are more likely to have bone cysts. In BSCL type I, females are at higher risk of developing diabetes mellitus and acanthosis nigricans than males, while in BSCL type II, males suffer from diabetes mellitus earlier than females. In addition, some significant correlations among BSCL-related phenotypes were identified. New candidate genes prediction through protein-protein interaction and phenotype-similarity was conducted and we found that CAV3, EBP, SNAP29, HK1, CHRM3, OBSL1 and DNAJC13 genes could be the pathogenic factors for BSCL. Particularly, CAV3 and EBP could be high-priority candidate genes contributing to pathogenesis of BSCL. Conclusions: Our study largely enhances the current knowledge of phenotypic and genotypic heterogeneity of BSCL and promotes the more comprehensive understanding of pathogenic mechanisms for BSCL.

Congenital generalized lipodystrophy in two siblings from Saudi Arabia: A case report

“…Heterozygous carriers are asymptomatic and are at increased risk of diabetes 14 . Most cases of AGPAT2 mutations are reported from consanguineous families in Brazil, Lebanon, and Scandinavia 3,12 . Most of the AGPAT2 mutations include frameshifts or altered mRNA splicing producing non‐functional enzyme 15 …”

“…14 Most cases of AGPAT2 mutations are reported from consanguineous families in Brazil, Lebanon, and Scandinavia. 3,12 Most of the AGPAT2 mutations include frameshifts or altered mRNA splicing producing nonfunctional enzyme. 15 Our two cases have pathogenic homozygous variants recognized at AGPAT2 gene, c.158del/p.(Gly53Alafs*8).…”

“…1,2 The two most common subtypes of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPLD). 3 CGLs, or Berardinelli-Seip congenital lipodystrophy (BSCL), are autosomal recessive disorders frequently recognized at birth or shortly thereafter. 4 At least four molecularly different genetic mutations of congenital lipodystrophy have been defined, including AGPAT2, BSCL2, CAV1, and polymerase I and transcript release factor (PTRF).…”

“… 1 , 2 The two most common subtypes of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPLD). 3 …”

“…Genetic lipodystrophies are inherited in autosomal recessive or autosomal dominant pattern 1,2 . The two most common subtypes of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPLD) 3 …”