Microcephaly is a disorder characterized by severe impairment in brain development, reduced brain and head size. Congenital severe microcephaly is very rare, and NDE1 deletion and genetic mutations are important contributors. Single nucleotide polymorphism (SNP) chromosomal microarray analysis (CMA) and muation screening of NDE1 gene were performed in an 8-month patient with severe congenital microcephaly, and/or his parents. Genetic studies found a 16p13.11 deletion containing NDE1 gene, and a novel NDE1 mutation c.555_556GC > CT on the non-deleted homolog, inherited from his phenotypically normal parents, respectively. The 2 bp nucleotide change results in a missense mutation p.K185 N and a nonsense mutation p.Q186X. We also conducted literaturte review to compare the clinical phenotypes of our patient to those of cases previously reported with NDE1 mutations, and found all patients had mental retardation, severe microcephaly, and corpus callosum agenesis. This is the first Chinese reported with microcephaly caused by NDE1 mutations. NDE1 is a critical pathogenetic gene in severe congenital microcephaly. Sequencing NDE1 and CMA in patients with severe congenital microcephaly may be warranted.

Background: BSNgene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship betweenBSNvariants and epilepsy.Methods: Whole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of unknown causes. Additional cases withBSNvariants were collected from China Epilepsy Gene V.1.0 Matching Platform. The Clinical Validity Framework of ClinGen was used to evaluate the relationship betweenBSNvariants and epilepsy.Results: Four pairs of compound heterozygous variants and one cosegregating heterozygous missense variant inBSNwere identified in five unrelated families. These variants presented statistically higher frequency in the case cohort than in controls. Additional two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant were identified in three unrelated cases from the gene matching platform, which were not present in the Genome Aggregation Database. The missense variants tended to be located in C-terminus, including the two monoallelic missense variants. Protein modelling showed that at least one missense variant in each pair of compound heterozygous variants had hydrogen bond alterations. Clinically, two cases were diagnosed as idiopathic generalised epilepsy, two as focal epilepsy and the remaining four as epilepsy with febrile seizures plus. Seven out of eight probands showed infancy or childhood-onset epilepsy. Eight out of 10 affected individuals had a history of febrile convulsions. All the cases were seizure-free. The cases with monoallelic variants achieved seizure-free without treatment or under monotherapy, while cases with biallelic missense variants mostly required combined therapy. The evidence from ClinGen Framework suggested an association betweenBSNvariants and epilepsy.Conclusion: TheBSNgene was potentially a novel candidate gene for epilepsy. The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.

Genetic polymorphisms in mTOR gene may be associated with cancer risk and clinical outcomes of cancer patients by affecting mTOR gene expression or its activation. However, inconsistent results have been reported. The aim of this study is to systematically evaluate the association between mTOR polymorphisms (rs2295080, rs2536 and rs11121704) and cancer risk as well as clinical outcome by a meta-analysis. We identified 10 eligible studies and extracted data by two investigators. Based on dominant and recessive models, odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by using Stata, version 11 to evaluate the association strength. Our meta-analysis results showed that the wild genotype TT of rs2295080 polymorphism was associated with increased cancer risk under dominant model (OR = 1.24, 95%CI: 1.12–1.36, p<0.0005) in Chinese but not with clinical outcome parameters, while the TT genotype of rs11121704 was associated with poor clinical outcome parameters (OR = 1.53, 95%CI: 1.01–2.32, p = 0.044), such as death, metastasis and resistance to chemotherapy. However, rs2536 may not influence cancer susceptibility. In conclusion, this meta-analysis indicated the common polymorphisms in mTOR gene might be genetic risk factors for the carcinogenesis and clinical outcomes of cancer patients. However, further investigation on large population and different ethnicities are warranted.

Spinal muscular atrophy (SMA) is one of the most common and severe genetic diseases. SMA carrier screening is an effective way to identify couples at risk of having affected children. Next-generation sequencing (NGS)-based expanded carrier screening could detect SMN1 gene copy number without extra experiment and with high cost performance. However, its performance has not been fully evaluated. Here we conducted a systematic comparative study to evaluate the performance of three common methods. 478 samples were analyzed with multiplex ligation probe amplification (MLPA), real-time quantitative polymerase chain reaction (qPCR) and NGS, simultaneously. Taking MLPA-based results as the reference, for 0 copy, 1 copy and ≥ 2 copy SMN1 analysis with NGS, the sensitivity, specificity and precision were all 100%. Using qPCR method, the sensitivity was 100%, 97.52% and 94.30%, respectively; 98.63%, 95.48% and 100% for specificity; and 72.72%, 88.72% and 100% for precision. NGS repeatability was higher than that of qPCR. Moreover, among three methods, NGS had the lowest retest rate. Thus, NGS is a relatively more reliable method for SMN1 gene copy number detection. In expanded carrier screening, compared with the combination of multiple methods, NGS method could reduce the test cost and simplify the screening process.