As a scientific community we assumed that exome sequencing will elucidate the basis of most heritable diseases. However, it turned out it was not the case; therefore, attention has been increasingly focused on the non-coding sequences that encompass 98% of the genome and may play an important regulatory function. The first WGS-based datasets have already been released including underrepresented populations. Although many databases contain pooled data from several cohorts, recently the importance of local databases has been highlighted. Genomic databases are not only collecting data but may also contribute to better diagnostics and therapies. They may find applications in population studies, rare diseases, oncology, pharmacogenetics, and infectious and inflammatory diseases. Further data may be analysed with Al technologies and in the context of other omics data. To exemplify their utility, we put a highlight on the Polish genome database and its practical application.

/pdf/wgs-data-collections-how-do-genomic-databases-transform-3gu06mx6.pdf

WGS Data Collections: How Do Genomic Databases Transform Medicine?

Abstract Currently, there is still a lack of novel and effective drug targets to improve the prognosis of hepatocellular carcinoma (HCC). Additionally, the role of CHEK2 in HCC has not been reported yet. The eQTLgen database and two HCC Genome-Wide Association Study (GWAS) datasets (ieu-b-4953, ICD10 C22.0) were used to find the drug target: CHEK2. Next, Colony, Edu, β-gal, and cell cycle analysis were facilitated to evaluate the role of CHEK2 knockout in HCC. In addition, Nultin-3 was added to evaluate the apoptosis of TP53-mutated HCC cells with CHEK2 knockout. Furthermore, MitoSox, electron microscopy, mitochondrial ATP, and NADH+/NADH levels were assessed in the CHEK2 knockout HCC cells with or without Metformin. Finally, cell-derived tumor xenograft was used to evaluate the role of CHEK2 knockout in vivo. We initially identified a potential drug target, CHEK2, through GWAS data analysis. Furthermore, we observed a significant upregulation of CHEK2 expression in HCC, which was found to be correlated with a poor prognosis. Subsequently, the results indicated that knocking out CHEK2 selectively affects the proliferation, cell cycle, senescence, and apoptosis of TP53-mutant HCC cells. Additionally, the introduction of Nultin-3 further intensified the functional impact on TP53-mutant cells. Then ClusterProfiler results showed high CHEK2 and TP53 mutation group was positively enriched in the mitochondrial ATP pathway. Then we used MitoSox, electron microscopy, mitochondrial ATP, and NADH + /NADH assay and found knockout of CHECK could induce the ATP pathway to inhibit the growth of HCC. Our research introduces a novel drug target for TP53-mutant HCC cells via mitochondrial ATP, addressing the limitation of Nultin-3 as a standalone treatment that does not induce tumor cell death. 

CHEK2 knockout is a therapeutic target for TP53-mutated hepatocellular carcinoma

Simple Summary Mutations in the FANCM gene may cause a particular type of breast cancer known as ER-negative. In this study, we describe the geographic distribution of 66 different FANCM mutations identified in 44,803 female breast cancer cases from Europe, USA, Canada and Australia. We found that the FANCM:p.Gln1701* mutation is most common in Northern Europe and has lower frequencies in Southern European countries. In contrast, the FANCM:p.Gly1906Alafs*12 mutation is most common in Southern Europe and rarer in Central and Northern Europe. We found that the FANCM:p.Arg658* mutation is most prevalent in Central Europe and that the FANCM:p.Gln498Thrfs*7 mutation originates from Lithuania. Finally, we showed that many and varied FANCM mutations are present in Southwestern and Central Europeans while a much more limited range of mutations is present in Northeastern Europeans. The knowledge of this geographic distribution of FANCM mutations is important to establish more efficient genetic testing strategies in specific populations. Abstract FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

/pdf/spectrum-and-frequency-of-germline-fancm-protein-truncating-3vyo6n59.pdf

Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases

Hereditary neuromuscular disorders (NMDs) are a broad group of clinically heterogeneous disorders with varying inheritance patterns, that are associated with over 500 implicated genes. In the context of a highly consanguineous Pakistani population, we expect that autosomal recessive NMDs may have a higher prevalence compared with patients of European descent. This is the first study to offer a detailed description of the spectrum of genes causing hereditary NMDs in the Pakistani population using NGS testing. To study the clinical and genetic profiles of patients presenting for evaluation of a hereditary neuromuscular disorder. This is a retrospective chart review of patients seen in the Neuromuscular Disorders Clinic and referred to the Genetics Clinic with a suspected hereditary neuromuscular disorder, between 2016 and 2020 at the Aga Khan University Hospital, Karachi and Mukhtiar A. Sheikh Hospital, Multan, Pakistan. The genetic testing for these patients included NGS-based single gene sequencing, NGS-based multi-gene panel and whole exome sequencing. In a total of 112 patients studied, 35 (31.3%) were female. The mean age of onset in all patients was 14.6 years (SD ±12.1 years), with the average age at presentation to the clinic of 22.4 years (SD ±14.10 years). Forty-seven (41.9%) patients had a positive genetic test result, 53 (47.3%) had one or more variants of uncertain significance (VUS), and 12 (10.7%) had a negative result. Upon further genotype-phenotype correlation and family segregation analysis, the diagnostic yield improved, with 59 (52.7%) patients reaching a diagnosis of a hereditary NMD. We also report probable founder variants in COL6A2, FKTN, GNE, and SGCB, previously reported in populations that have possible shared ancestry with the Pakistani population. Our findings reemphasizes that the rate of VUSs can be reduced by clinical correlation and family segregation studies.

The spectrum of hereditary neuromuscular disorders in the Pakistani population.

European collaboration on genetic tumour risk syndromes.

Spectrum and frequency of CHEK2 variants in breast cancer affected and general population in the Baltic states region, initial results and literature review.

Background and Objectives Genetic testing has become an integral part of health care, allowing the confirmation of thousands of hereditary diseases, including neuromuscular disorders (NMDs). The reported average prevalence of individual inherited NMDs is 3.7–4.99 per 10,000. This number varies greatly in the selected populations after applying population-wide studies. The aim of this study was to evaluate the effect of genetic analysis as the first-tier test in patients with NMD and to calculate the disease prevalence and allelic frequencies for reoccurring genetic variants. Methods Patients with NMD from Latvia with molecular tests confirming their diagnosis in 2008–2020 were included in this retrospective study. Results Diagnosis was confirmed in 153 unique cases of all persons tested. Next-generation sequencing resulted in a detection rate of 37%. Two of the most common childhood-onset NMDs in our population were spinal muscular atrophy and dystrophinopathies, with a birth prevalence of 1.01 per 10,000 newborns and 2.08 per 10,000 (male newborn population), respectively. The calculated point prevalence was 0.079 per 10,000 for facioscapulohumeral muscular dystrophy type 1, 0.078 per 10,000 for limb-girdle muscular dystrophy, 0.073 per 10,000 for nondystrophic congenital myotonia, 0.052 per 10,000 for spinobulbar muscular atrophy, and 0.047 per 10,000 for type 1 myotonic dystrophy. Discussion DNA diagnostics is a successful approach. The carrier frequencies of the common CAPN3, FKRP, SPG11, and HINT1 gene variants as well as that of the SMN1 gene exon 7 deletion in the population of Latvia are comparable with data from Europe. The carrier frequency of the CLCN1 gene variant c.2680C>T p.(Arg894Ter) is 2.11%, and consequently, congenital myotonia is the most frequent NMD in our population.

https://ng.neurology.org/content/nng/8/3/e685.full.pdf

Overview of Neuromuscular Disorder Molecular Diagnostic Experience for the Population of Latvia

Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss‐of‐function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal‐type‐related inhibitor (LEKTI).

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/pai.13937

Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population

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Spectrum and frequency of CHEK2 variants in breast cancer affected and general population in the Baltic states region, initial results and literature review.

Overview of Neuromuscular Disorder Molecular Diagnostic Experience for the Population of Latvia

Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population