Dataset Information

Unraveling the genetic causes in large pedigrees with gout by whole?exome sequencing.

ABSTRACT: Gout is a common type of inflammatory arthritis that is clinically and genetically heterogeneous. The genetic aetiology remains unclear, and mainly relies on previous genome?wide association studies focused on sporadic cases. The present study aimed to identify the genetic basis of gout in three families using whole?exome sequencing (WES). WES was performed in the probands, and family members were involved in the co?segregation analysis. In total, three deleterious rare or novel missense mutations were identified in ATP?binding cassette super?family G member 2 (ABCG2), protein kinase CGMP?dependent 2 (PRKG2) and adrenoceptor ?3 (ADRB3) genes in three different families. In addition, certain gout?associated candidate genes were revealed to be shared among the co?expression and protein?protein interaction (PPI) networks of ABCG2, PRKG2 and ADRB3. Furthermore, the disease ontology analysis of the genes present in the co?expression network exhibited significant (P<0.05) enrichment in hyperuricemia, gout, cardiovascular system disease and metabolic disease. In addition, genes involved in the PPI network were significantly enriched in the purine nucleoside monophosphate biosynthetic process, urate transport and biological processes associated with glycose metabolism. Collectively, to the best of our knowledge, the present study was the first to use WES to identify three candidate rare or novel deleterious mutations in three families with gout. The present results provided novel insights that may improve the current understanding of the molecular genetic basis underlying gout. Importantly, the present results may facilitate the improvement of clinical diagnosis and the development of novel personalized therapies.

SUBMITTER: Xia X

PROVIDER: S-EPMC7053847 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Unraveling the genetic causes in large pedigrees with gout by whole‑exome sequencing.

Xia Xiaoru X Jin Jing J Chen Zhen-Ji ZJ Zhou Zhenni Z Chen Hui H Zhang Chunwu C Zhang Linhua L Sun Li L

International journal of molecular medicine 20200213 4

Gout is a common type of inflammatory arthritis that is clinically and genetically heterogeneous. The genetic aetiology remains unclear, and mainly relies on previous genome‑wide association studies focused on sporadic cases. The present study aimed to identify the genetic basis of gout in three families using whole‑exome sequencing (WES). WES was performed in the probands, and family members were involved in the co‑segregation analysis. In total, three deleterious rare or novel missense mutatio ...[more]

PMID: 32124961

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Project description:BACKGROUND:Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients. AIM:To identify genetic risk factors in two large families with unexplained hereditary VTE. METHODS:We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls. RESULTS:Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (PLEKHH2 NM_172069:c.3105T>C, LRPPRC rs372371276, SRBD1 rs34959371), 5q35.2 (UNC5A NM_133369.2:c.1869+23C>A), and 17q25.1 (GPRC5C rs142232982, RAB37 rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the UNC5A variant was present. CONCLUSION:Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects.

Dataset Information

Unraveling the genetic causes in large pedigrees with gout by whole?exome sequencing.

Publications

Unraveling the genetic causes in large pedigrees with gout by whole‑exome sequencing.

Similar Datasets

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