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. 2020 Apr 29;15(1):108.
doi: 10.1186/s13023-020-01383-y.

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

Meng Ren  1 , Jingru Shi  1 , Jinmeng Jia  1 , Yongli Guo  2   3   4 , Xin Ni  5   6   7 , Tieliu Shi  8   9
Affiliations

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

Meng Ren et al. Orphanet J Rare Dis. .

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 genotype-phenotype 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.

Keywords: Berardinelli-Seip congenital lipodystrophy; Gene prediction; Genotype; Phenotype; Phenotype-similarity; Protein-protein interaction.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a A detailed flow chart for the new candidate gene prediction. The green box is the method of protein-protein interaction, and the yellow box is the method of phenotype-similarity. b The sub-network centered on causative proteins. Nodes in red represent the causative proteins. Nodes in green and yellow represent the BSCL-related proteins. Nodes in yellow represent the new candidate proteins we predicted. c BSCL-related phenotypes associated with causative genes and candidate genes
Fig. 2
Fig. 2
a A bar chart showing the differential distribution of causative genes in different ethnicities. b A heatmap used to show the correlation between any two phenotypes. A grid in red indicates that the relationship it represents has passed the statistical test. The value on the grid is used to measure the degree of correlation. c A line graph used to present the expression abundance of causative genes and gene EBP in human tissues
See this image and copyright information in PMC

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