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BACKGROUND Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by a deficiency of the enzyme α-galactosidase A. CASE SUMMARY Herein, we analyzed a four-generation Chinese family. The proband is a 57-year-old woman who was diagnosed with left ventricular hypertrophy and atrial fibrillation 7 years ago. Echocardiography showed an end-diastolic diameter of the interventricular septum of 19.9 mm, left ventricular end-diastolic diameter of 63.1 mm, and moderate-to-severe mitral regurgitation. Cardiac magnetic resonance indicated an enlarged left heart and right atrium, decreased left ventricular systolic and diastolic function, a left ventricular ejection fraction of 20%, and thickening of the left ventricular septum. In March 2019, gene and enzyme activity tests confirmed the diagnosis of FD. Her son was diagnosed with FD after gene and enzyme activity assay, and was prescribed agalsidase-β for enzyme replacement therapy in July 2020. Two sisters of the proband were also diagnosed with FD by genetic testing. Both of them had a history of atrial fibrillation. CONCLUSION A novel mutation was identified in a Chinese family with FD, in which the male patient had a low level of enzyme activity, early-onset, and severe organ involvement. Comprehensive analysis of clinical phenotype genetic testing and enzyme activity testing helped in the diagnosis and treatment of this FD family.

WES raw data for Patients P1, P2 and P3., This research was funded by the National Science Centre in Poland (grant OPUS No 2016/23/B/NZ5/00065).

Objective To investigate the mutations in the tissue DNA and plasma circulating tumor DNA (ctDNA) from patients with prostate cancer, and analyze their association with clinical characteristics and treatment. Methods Based on probe hybridization capture and Illumina high-throughput sequencing, a targeted second-generation sequencing was used to analyze the mutations in 31 tumor tissues and 32 peripheral blood specimens from 46 patients with pathologically diagnosed prostate cancer. The tumor tissues and peripheral blood specimens were sequenced in the whole exons area and part of the introns area of 1 021 genes for 4 types of mutations (point mutation, loss/insert of small fragments, copy number variation and currently known fusion genes). Results The most frequently mutated gene was TP53 (29.0%, 9/31), followed by CDK12 (22.6%, 7/31), FOXA1 (22.6%, 7/31) and JAK1 (16.1%, 5/31) in 31 tissue samples. The most common mutant genes in the 32 blood samples were AR (34.3%, 11/32), APC (25.0%, 8/32), CDK12 (18.8%, 6/32), DNMT3a (18.8%, 6/32) and TP53 (18.8%, 6/32). TMPRSS2-ERG fusion gene was detected in 13.0% (6/46) of the 46 patients. One patient had TMPRSS2-ERG, VEGFA-TMPRSS2, and ERG-VEGFA fusion mutations simultaneously. The somatic mutation of homologous recombination (HR) associated genes were found in 21.7% (10/46) of all the patients, and those with germline mutations in the HR gene accounted for 8.7% (4/46) of all the patients. Moreover, the patients with HR gene mutations (either germline or somatic), especially those with germline mutations, had younger onset-age, higher Gleason score, and more metastases. Conclusion Gene mutation can be detected from both blood ctDNA and traditional tissue DNA. Dynamic blood ctDNA testing can monitor the changes in gene spectrum of prostate cancer, and is helpful to adjust treatment scheme in time.

Whole exon sequencing is a genomic analysis method that uses sequence capture technology to capture and enrich the whole genome exon region DNA for high-throughput sequencing. This technology has been applied to gene diagnosis and treatment of various complex diseases. At present, the pathogenesis of breast cancer has not been clearly elucidated, and the activation of oncogenes and the inactivation of tumor suppressor genes caused by gene mutation of somatic cells play a crucial role in the development of breast cancer. In recent years, numerous research groups have carried out a large number of whole exon sequencing researches, found and identified many genetic mutations associated with complex diseases/traits, which provide important clues for the study of the pathogenesis of complex diseases. This paper reviews the pathogenesis and diagnosis and treatment of breast cancer by whole exon sequencing.

Knobloch syndrome is an inherited disorder characterized by high myopia, retinal detachment, and occipital defects. Disease-causing mutations have been identified in the COL18A1 gene. This study aimed to investigate novel variants of COL18A1 in Knobloch syndrome and describe the associated phenotypes in Chinese patients. We reported six patients with Knobloch syndrome from four unrelated families in whom we identified five novel COL18A1 mutations. Clinical examination showed that all probands presented with high myopia, chorioretinal atrophy, and macular defects; one exhibited rhegmatogenous retinal detachment in one eye. Occipital defects were detected in one patient.

Objective: 1q44 microdeletion syndrome is difficult to diagnose due to the wide phenotypic spectrum and strong genetic heterogeneity. We explore the correlation between the chromosome microdeletions and phenotype in a child with 1q44 microdeletion syndrome, we collected the clinical features of the patient and combined them with adjacent copy number variation (CNV) regions previously reported.Methods: We collected the full medical history of the patient and summarized her clinical symptoms. Whole-exome sequencing (WES) and CapCNV analysis were performed with DNA extracted from both the patient's and her parents' peripheral blood samples. Fluorescent quantitative PCR (q-PCR) was performed for the use of verification to the CNV regions.Results: A 28.7 KB microdeletion was detected in the 1q44 region by whole-exome sequencing and low-depth whole-genome sequencing. The deleted region included the genes COX20 and HNRNPU. As verification, karyotype analysis showed no abnormality, and the results of qPCR were consistent with that of whole-exome sequencing and CapCNV analysis.Conclusion: The patient was diagnosed with 1q44 microdeletion syndrome with clinical and genetic analysis. Analyzing both whole-exome sequencing and CapCNV analysis can not only improve the diagnostic rate of clinically suspected syndromes that present with intellectual disability (ID) and multiple malformations but also support further study of the correlation between CNVs and clinical phenotypes. This study lays the foundation for the further study of the pathogenesis of complex diseases.

Rationale: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder, which is mostly reported to be associated with the mutation of genes involved in the Wnt signaling pathway related to β-catenin. To the best of our knowledge, the involvement of Adams-Oliver syndrome (AOS) genes in FEVR patients have not been reported before. Patient concerns: Two patients with FEVR presented with microcephaly. One of them showed slight scarring of the scalp vertex which is a typical manifestation of AOS. The whole exon sequencing confirmed the diagnosis of AOS with 2 AOS-gene mutations at DOCK6 and ARHGAP31. Further clinical examination revealed that their parents with the same mutations showed FEVR-like vascular anomalies. Diagnosis: Both patients were diagnosed with AOS through whole exon sequencing, and they presented with some FEVR-like retinopathy including retinal detachment. Interventions: Both patients received vitrectomy for tractional retinal detachment with proliferative vitreoretinopathy. During the follow-up, 1 patient received additional laser photocoagulation for tractional retinal detachment. Outcomes: The 2 patients remained stable in the latest follow up after the treatment. Lessons: Microcephaly could be associated with some form of retinopathy. We proposed that mutation of DOCK6 and ARHGAP31 genes could be the possible cause of FEVR associated with microcephaly. Our study suggested that these genes may be candidate genes of FEVR.

Neoadjuvant chemotherapy (NACT) remains an attractive alternative for controlling locally advanced cervical cancer. However, approximately 15–34% of women do not respond to induction therapy. To develop a risk stratification tool, 56 patients with stage IB‐IIB cervical cancer are included in 2 research centers from the discovery cohort. Patient‐specific somatic mutations led to NACT non‐responsiveness are identified by whole‐exome sequencing. Next, CRISPR/Cas9‐based library screenings are performed based on these genes to confirm their biological contribution to drug resistance. A 15‐gene classifier is developed by generalized linear regression analysis combined with the logistic regression model. In an independent validation cohort of 102 patients, the classifier showed good predictive ability with an area under the curve of 0.80 (95% confidence interval (CI), 0.69–0.91). Furthermore, the 15‐gene classifier is significantly associated with patient responsiveness to NACT in both univariate (odds ratio, 10.8; 95% CI, 3.55–32.86; p = 2.8 × 10−5) and multivariate analysis (odds ratio, 17.34; 95% CI, 4.04–74.40; p = 1.23 × 10−4) in the validation set. In conclusion, the 15‐gene classifier can accurately predict the clinical response to NACT before treatment, representing a promising approach for guiding the selection of appropriate treatment strategies for locally advanced cervical cancer., In a multicenter study of 158 patients with stage IB‐IIB cervical cancer, a 15‐core‐gene classifier is developed by integrated analysis of whole‐exome sequencing and CRISPR library screening. By predicting cervical cancer patients who would benefit from neoadjuvant chemotherapy, the classifier has the potential to guide the proper selection of treatment modalities, implicating a significant advance toward individualizing therapy.