Medical Genetics

Epigenetic modifications are known to be effective in the severity and mortality rate of SARS-CoV-2 infection. N6-methyladenosin (m6A) is a posttranscriptional modification that is carried out by m6A methyltransferases (METTL3, METTL14, and WTAP). This modification is effective in the formation of a natural immune response in the relationship between the viral genome and the host cell. In this study, the relationship between clinical severity and METTL3, METTL14, WTAP expression levels in Covid-19 patients was studied for the first time. Also, patients' D-dimer, ferritin, and C-reactive protein values were compared with these gene expression levels. Total RNA was extracted from blood samples of 100 volunteers and gene expressions were measured using a quantitative real-time polymerase chain reaction. It was determined that METTL3 (p < 0.001) and METTL14 (p = 0.005) genes were statistically significant between case and control. In addition, METTL14 (p = 0.007) and WTAP (p = 0.015) gene expressions were significantly increased in patients with severe disease. METTL14 was statistically significant between the male patients and the control (fold change = 63.87, p = 0.015). Overexpression of the METTL14 gene may have resulted in higher clinical severity in males. Our results demonstrate that host N6-methyladenosine (m6A) methyltransferases may be effective in the development of SARS-CoV-2 infection and prognosis of the disease.

Resulting from several basic scientific disciplines, genetics has made impressive progress in the last century by discoveries of the heredity rules and genome structure, and by identification of the genes that determine the occurrence and characteristics of human diseases. In Croatia, the development of genetics began in the middle of the past century by the pioneering work of clinicians and basic scientists, which resulted in significant development of this scientific discipline that has quickly found its practical application in clinical genetics-cytogenetics, molecular genetics and prenatal diagnosis. The rapid advancement of technology and knowledge of genetics in recent decades has led to the development of genomics and related disciplines, entering the revolutionary new era of personalized medicine. Currently, much more data can be collected than interpreted. The data of electronic medical records, genomics, epigenetics, proteomics, meta- bolomics and microbiomics should be in...

Autoimmune Addison&#39;s disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to A...

The Saguenay–Lac-Saint-Jean (SLSJ) region located in the province of Quebec was settled in the 19th century by pioneers issued from successive migration waves starting in France in the 17th century and continuing within Quebec until the beginning of the 20th century. The genetic structure of the SLSJ population is considered to be the product of a triple founder effect and is characterised by a higher prevalence of some rare genetic diseases. Several studies were performed to elucidate the historical, demographic and genetic background of current SLSJ inhabitants to assess the origins of these rare disorders and their distribution in the population. Thanks to the development of new sequencing technologies, the genes and the variants responsible for the most prevalent conditions were identified. Combined with other resources such as the BALSAC population database, identifying the causal genes and the pathogenic variants allowed to assess the impacts of some of these founder mutations...

The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendation (CADRe) framework proposes that key components of informed consent for genetic testing can be covered with a targeted discussion for many conditions rather than a time-intensive traditional genetic counseling approach. We surveyed US genetics professionals (medical geneticists and genetic counselors) on their response to scenarios that proposed core informed consent concepts for clinical genetic testing developed in a prior expert consensus process. The anonymous online survey included responses to 3 (of 6 possible) different clinical scenarios that summarized the application of the core concepts. There was a binary (yes/no) question asking respondents whether they agreed the scenarios included the minimum necessary and critical educational concepts to allow an informed decision. Respondents then provided open-ended feedback on what concepts were missing or could be removed. At least one scenario was comple...

To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

Gorlin-Goltz syndrome (GGS) or nevoid basal cell carcinoma syndrome is a rare tumour-overgrowth syndrome associated with multiple developmental anomalies and a wide variety of tumours. Here, we describe a case of a man aged 23 years with GGS with bilateral giant tumours adjacent to both adrenals that raised the suspicion of malignancy on imaging. Histological analysis of both surgically resected tumours revealed perivascular epitheloid cell tumours (PEComas) that were independent of the adrenals. Exome sequencing of the patient’s blood sample revealed a novel germline heterozygous frameshift mutation in the PTCH1 gene. As a second hit, a somatic five nucleotide long deletion in the PTCH1 gene was demonstrated in the tumour DNA of both PEComas. To the best of our knowledge, this is the first report on PEComa in GGS, and this finding also raises the potential relevance of PTCH1 mutations and altered sonic hedgehog signalling in PEComa pathogenesis. The presence of the same somatic mut...

BackgroundCockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS.Methods and resultsWe assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-...

Much of the current interest in genetics stems from the Human Genome Project. Although the project will accelerate the identification of disease-related genes, as currently formulated it may retard discovery of gene function and effective treatments, thereby prolonging the stage in which people at risk of genetic diseases can be identified but not treated. This stage is fraught with ethical problems. The project&#39;s goal of sequencing the entire human genome could also detract from basic biological research, as could the growing interest of universities in biotechnology transfer to the commercial sector.

With the identification of the cystic fibrosis (CF) gene and its major mutations in 1989, there has been considerable debate among health professionals as to whether population‐based carrier testing should be instituted. This paper presents the results of a survey to determine the attitudes of physicians and genetics professionals towards CF carrier testing. Factors associated with differences in attitudes also were examined.A questionnaire was mailed to primary care physicians and psychiatrists in 10 states who graduated from medical school between 1950 and 1985. For comparison, medical geneticists and genetic counselors in the same states also received the questionnaire.A total of 1,140 primary care physicians and psychiatrists (64.8%) and 280 medical geneticists and genetic counselors (79.1%) responded. Although 92% of respondents believed that a couple should be tested after asking about a test that detected 80% of carriers, only 43.9% of respondents believed such a test should ...