A novel mutation alters GNE bifunctional enzyme activity and leads to familial inherited GNE diseases.

Distal myopathies are a group of rare heterogeneous diseases that are mostly caused by genetic factors. At least 20 genes have been associated with distal myopathies. We performed whole-exome sequencing to identify the genetic cause of disease in a family with distal myopathy. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we analyzed the sequencing results and screened suspicious mutations based on mutation frequency, functional impact, and disease inheritance pattern. The harmfulness of the mutations was predicted using bioinformatics methods, and the pathogenic mutations were determined. We identified a novel amino acid mutation (NP_005467.1:p.S663L) on the GNE gene that may cause familial distal myopathy. This mutation is the result of the simultaneous mutation of two adjacent nucleotides (c.1988C > T, c.1989C > A) in the codon. First, we measured the mRNA and protein expression of the GNE gene in the lymphoblastoid cell lines (LCLs) of the probands and their family members. Second, GNE vectors carrying the novel mutation, two other known pathogenic mutations, and the wild-type gene were constructed and transfected into HEK293T cells. The enzymatic activity of these GNE variants was investigated and showed that the p.S663L mutation significantly reduced the activity of the bifunctional GNE enzyme without altering the expression level of the GNE protein. Furthermore, the mutation may also alter the immunogenicity of the 3' end of the GNE protein, potentially affecting its oligomer formation. In this study, a novel GNE gene mutation that may cause distal myopathy was identified, expanding the spectrum of genetic mutations associated with this disease.

Comprehensive research on the distribution of HLA-DRB1 in Chinese populations.

By presenting antigen peptides, HLA-DRB1 plays an important role in the immune system. However, the allele frequency of HLA-DRB1 exon 2 across China has not been comprehensively studied, especially in minority populations. We sampled 3757 individuals from 59 population. The HLA-DRB1 region from 212 to 463 bp (NM_002124.4 exon 2) in each population was sequenced by Sanger sequencing and genotyped via SBTengine® software, and the allele frequency was calculated by GenAlEx 6.5. Eighty-two DRB1 alleles were identified. The expected heterozygosity of DRB1 was lower in the south than in the north, which was inconsistent with the Y chromosome and mitochondrial DNA results. The Mantel test and nonparametric correlation analysis showed that the correlations of the genetic distance with geographical distance and of DRB1 allele frequencies with latitude weakened after the southern and northern groups were considered separately. Principal coordinate analysis showed that populations speaking the same languages were not codistributed. Compared with other genetic markers, the distribution of DRB1 seems less affected by geographic distance and ethnic origin. Local factors such as gene flow with neighbouring populations, geographic isolation or natural selection are important forces shaping the DRB1 gene pool of local populations.

Impact of ultrasonography on identifying noninvasive prenatal screening false-negative aneuploidy.

BACKGROUND: To evaluate the impact of ultrasonography on identifying noninvasive prenatal screening (NIPS) false-negative aneuploidy. METHODS: Analysis of large population-based NIPS false-negative aneuploidy data comprising karyotypes, clinical outcomes, and ultrasound results. RESULTS: From December 2010 to July 2018, a total of 3,320,457 pregnancies were screened by NIPS performed in BGI; among them, 69 NIPS false-negative aneuploidy cases with informed consent were confirmed, and ultrasound examination data for 48 cases were not available. Of the 21 cases with ultrasound results, 19 (90.5%) had various abnormalities on ultrasound, and two (9.5%) cases were shown to be normal on ultrasound. Additionally, six of seven live-born fetuses (approximately 85.7%) were found to have abnormalities on ultrasound. Ventricular septal defects constituted the most frequently observed ultrasound abnormality type among the 21 NIPS false-negative aneuploidy cases. CONCLUSION: Application of NIPS has increased rapidly worldwide and now accounts for a large proportion of prenatal screening tests in China. This study suggests that ISUOG guideline should be followed practically, and structural abnormal ultrasound findings should not be neglected, even when NIPS produces a negative result. Combining NIPS with an ultrasound examination can further reduce the incidence of live births with aneuploidy.