Functional characterization of
            <i>CEP250</i>
            variant identified in nonsyndromic retinitis pigmentosa

Huang, Xiu‐Feng; Xiang, Lan; Fang, Xiaolong; Liu, Weiqin; Zhuang, Youyuan; Chen, Zhen-Ji; Shen, Ren‐Juan; Wan, Cheng; Han, Ru-Yi; Zheng, Simin; Chen, Xue-Jiao; Liu, Xiaoling; Jin, Zi‐Bing

doi:10.1002/humu.23759

Cited by 23 publications

(29 citation statements)

References 41 publications

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“…Firstly, no functional genomics studies were performed in the present study. Experimental validations are essential to determine if interesting variants are indeed responsible for clinical symptoms [50,51]. For example, a recent study demonstrates the rare variants of ABCG2 at both the clinical level and the functional level by complex approach [52].…”

Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

Huang

Sun

Zhang

et al. 2020

BioMed Research International

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Gout is a common inflammatory arthritis triggered by monosodium urate deposition after longstanding hyperuricemia. In the general community, the disease is largely polygenic in genetic architecture, with many polymorphisms having been identified in gout or urate-associated traits. In a small proportion of cases, rare high penetrant mutations associated with monogenic segregation of the disease in families have been demonstrated to be disease causative. In this study, we recruited a two-generation pedigree with early-onset gout. To elucidate the genetic predisposition, whole-exome sequencing (WES) was performed. After comprehensive variant analyses and cosegregation testing, we identified a missense variant (c.277C>A, p.L93M) in SLC16A9, an extremely rare variant in genetic databases. Moreover, in silico assessments showed strong pathogenicity. This variant cosegregated with the disease phenotype perfectly in the family and is located in a highly conserved functional domain. A few studies supported our results of the association between SLC16A9 and gout and serum urate levels. In conclusion, we provide the first evidence for the association of rare missense in SLC16A9 with early-onset gout. These findings not only expand our current understanding of gout but also may have further implications for the treatment and prevention of gout.

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Section: Discussionmentioning

confidence: 99%

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

Huang

Sun

Zhang

et al. 2020

BioMed Research International

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“…A previous complex segregation and linkage analysis of familial gout revealed an autosomal-arbitrary major gene model (20). WES is able to provide insights into the pathogeny of hereditary diseases and extend molecular diagnosis (45)(46)(47)(48). Therefore, WES was performed in three families with gout.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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 β3 (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.

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“…Instead, we employed the targeted nextgeneration sequencing method to test all of the known skeletal, muscle, and nervous system monogenic diseases, and used PCR to verify the mutation sites of the family. The next-generation sequencing method has proven to be a very powerful approach to identify mutations for rare diseases (Huang et al, 2018(Huang et al, , 2019. The sequencing results showed that the patient had compound heterozygous mutations of p.S79L (c.236C > T) and p.T489S (c.1466C > G).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Compound Heterozygous Mutations in the GAN Gene of a Chinese Patient Diagnosed With Giant Axonal Neuropathy

Yang

et al. 2020

Front. Neurosci.

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Giant axonal neuropathy (GAN) is a very rare autosomal recessive disorder characterized by abnormally large and dysfunctional neuronal axons. Mutations in the GAN gene have been identified as the cause of this disorder. In this report, we performed a detailed phenotypic assessment of a Chinese patient with GAN. An array-based exon capture test and targeted next-generation sequencing were used to detect the suspected mutation sites. Compound heterozygous mutations of p.S79L (c.236C > T) in the BTB domain and p.T489S (c.1466C > G) in the kelch domain were identified in the proband's genome. S79L was a known mutation, and T489S was reported for the first time. The p.S79L and p.T489S were confirmed in the proband's mother and father, respectively. Both mutations were located in highly conserved regions and affected the predicted protein crystal structures. The proband's sural biopsy revealed the classical GAN phenotype of swollen axons filled with closely packed neurofilaments. The combined application of the next-generation sequencing platform and bioinformatics analyses was an effective method for diagnosing GAN. The novel compound mutations of S79L and T489S in the GAN gene were likely the cause of the patient's GAN symptoms. Our findings enrich the spectrum of mutations associated with this rare type of axonopathy.

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Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa

Cited by 23 publications

References 41 publications

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

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

Identification of Novel Compound Heterozygous Mutations in the GAN Gene of a Chinese Patient Diagnosed With Giant Axonal Neuropathy

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