自引率: 7.2%
被引量: 13747
通过率: 暂无数据
审稿周期: 1
版面费用: 暂无数据
国人发稿量: 14
投稿须知/期刊简介:
Human Mutation is a peer-reviewed journal that offers publication of original Research Articles Methods Mutation Updates Reviews Database Articles Mutations in Brief (MIBs) Rapid Communications and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences reports of SNPs demonstrated as valuable for genomic analysis descriptions of new molecular detection methods and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level reported in the context of mutation investigation may be considered. The journal provides a unique forum for the exchange of ideas methods and applications of interest to molecular human and medical geneticists in academic industrial and clinical research settings worldwide.
期刊描述简介:
Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.
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Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation.
被引量：5 发表：1970
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Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest.
The subcortical maternal complex (SCMC), composed of several maternal-effect genes, is vital for the development of oocytes and early embryos. Variants of SCMC-encoding genes (NLRP2, NLRP5, TLE6, PADI6, and KHDC3L, but not OOEP and ZBED3) are associated with human oocyte maturation dysfunction, fertilization failure, and early embryonic arrest. In this study, we enrolled 118 Chinese patients who experienced recurrent preimplantation embryonic arrest during assisted reproductive technology treatments and performed whole-exome sequencing. We discovered compound heterozygous missense variants (c.110G>C and c.109C>G) in the OOEP gene in one patient who experienced recurrent preimplantation embryonic arrest. Arrested embryos from this affected patient were analyzed by single-cell RNA sequencing, which showed a downregulated transcriptome. In addition, six novel NLRP5 variants (c.971T>A, c.3341T>C, c.1575_1576delAG, c.1830_1831delGT, c.1202C>T, and c.2378T>G) were identified in four patients with arrested and severely fragmented embryos. These suspicious mutations were examined by in vitro studies in HEK293T cells. Western blot analysis and immunofluorescence experiments showed that OOEP and partial NLRP5 mutations caused decreased protein levels. Our findings first demonstrated that biallelic variants in OOEP gene could also cause human early embryonic arrest, similar to other SCMC components. We expanded the genetic mutation spectrum of SCMC genes related to early embryogenesis in humans, especially early embryonic arrest.
被引量：9 发表：1970
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Benchmarking deep learning splice prediction tools using functional splice assays.
Hereditary disorders are frequently caused by genetic variants that affect pre-messenger RNA splicing. Though genetic variants in the canonical splice motifs are almost always disrupting splicing, the pathogenicity of variants in the noncanonical splice sites (NCSS) and deep intronic (DI) regions are difficult to predict. Multiple splice prediction tools have been developed for this purpose, with the latest tools employing deep learning algorithms. We benchmarked established and deep learning splice prediction tools on published gold standard sets of 71 NCSS and 81 DI variants in the ABCA4 gene and 61 NCSS variants in the MYBPC3 gene with functional assessment in midigene and minigene splice assays. The selection of splice prediction tools included CADD, DSSP, GeneSplicer, MaxEntScan, MMSplice, NNSPLICE, SPIDEX, SpliceAI, SpliceRover, and SpliceSiteFinder-like. The best-performing splice prediction tool for the different variants was SpliceRover for ABCA4 NCSS variants, SpliceAI for ABCA4 DI variants, and the Alamut 3/4 consensus approach (GeneSplicer, MaxEntScacn, NNSPLICE and SpliceSiteFinder-like) for NCSS variants in MYBPC3 based on the area under the receiver operator curve. Overall, the performance in a real-time clinical setting is much more modest than reported by the developers of the tools.
被引量：46 发表：1970
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Comparative analysis of rare EDAR mutations and tooth agenesis pattern in EDAR- and EDA-associated nonsyndromic oligodontia.
Nonsyndromic oligodontia is a rare congenital anomaly. Mutations in the ectodysplasin A receptor (EDAR) gene are the primary cause of hypohidrotic ectodermal dysplasia but are rarely reported in nonsyndromic oligodontia. This study investigated EDAR mutations in multiplex nonsyndromic oligodontia and comparatively analyzed the EDAR- and EDA-related tooth agenesis patterns. Mutation screening was carried out using whole-exome sequencing and familial segregation. Evolutionary conservation and conformational analyses were used to evaluate the potential pathogenic influence of EDAR mutants. EDAR mutations were found to occur in 10.7% of nonsyndromic oligodontia cases. We reported seven heterozygous mutations of EDAR, including five novel mutations (c.404G>A, c.871G>A, c.43G>A, c.1072C>T, and c.1109T>C) and two known mutations (c.319A>G and c.1138A>C). Genotype-phenotype correlation analysis demonstrated that the EDAR-related tooth agenesis pattern was markedly different from EDA. The mandibular second premolars were most frequently missing (57.69%) in EDAR-mutated patients. Our results provide new evidence for the genotypic study of nonsyndromic oligodontia and suggest that EDAR haploinsufficiency results in nonsyndromic tooth agenesis. Furthermore, the distinct pattern between EDAR- and EDA-related tooth agenesis can be used as a guide for mutation screening during the clinical genetic diagnosis of this genetic disorder.
被引量：8 发表：1970
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EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion-Almeida type.
Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion-Almeida type (MFDGA). MFDGA-associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss-of-function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss-of-function are self-evident, the mechanisms by which missense variants are disease-causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss-of-function. Only four of 19 assessed missense variants cause EFTUD2 loss-of-function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre-messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory-based validation of bioinformatic predictions for EFTUD2 missense variants.
被引量：11 发表：1970
