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Background: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2-3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population., Methods: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes., Results: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859-7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group., Conclusion: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years ( p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS.

Background: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information., Methods: Data were collected via a structured questionnaire. Sequencing was performed in these patients mostly due to diagnostic purpose. A little more than half of the AXIN2 variant carriers were identified by NGS; other six were family members., Results: Here, we report 13 individuals with a heterozygous AXIN2 pathogenic/likely pathogenic variant who have a variable expression of oligodontia-colorectal cancer syndrome (OMIM 608615) or oligodontia-cancer predisposition syndrome (ORPHA 300576). Three individuals from one family also had cleft palate, which might represent a new clinical feature of AXIN2 phenotype, also given the fact that AXIN2 polymorphisms have been found in association with oral clefting in population studies. AXIN2 has already been added to multigene cancer panel tests; further research should be conducted to determine whether it should be added to cleft lip/palate multigene panels., Conclusion: More clarity about oligodontia-colorectal cancer syndrome, about the variable expression, and associated cancer risks is needed to improve clinical management and to establish guidelines for surveillance. We collected information about the surveillance that was advised, which might support clinical management of these patients., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

TATA-binding protein associated factor 4 (TAF4) is a subunit of the Transcription Factor IID (TFIID) complex, a central player in transcription initiation. Other members of this multimeric complex have been implicated previously as monogenic disease genes in human developmental disorders. TAF4 has not been described to date as a monogenic disease gene. We here present a cohort of eight individuals, each carrying de novo putative loss-of-function (pLoF) variants in TAF4 and expressing phenotypes consistent with a neuro-developmental disorder (NDD). Common features include intellectual disability, abnormal behavior, and facial dysmorphisms. We propose TAF4 as a novel dominant disease gene for NDD, and coin this novel disorder "TAF4-related NDD" (T4NDD). We place T4NDD in the context of other disorders related to TFIID subunits, revealing shared features of T4NDD with other TAF-opathies., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study., Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age., Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2., Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Colorectal cancer (CRC) is the third most common cancer in Estonia in both women and men. According to the Estonian National Institute for Health Development, in 2017, there were 357 new colon cancer only cases in women and 282 in men. For colorectal cancer, the number for men and women altogether was 1040 in the same year. In 2018, there were over 1.8 million new cases worldwide. The Mayo Clinic found in a prospective, two-year multi-site study of CRC patients that 15.5% of patients carried pathogenic germline variants (PGV), using an >80 gene Next Generation Sequencing (NGS) panel. Material and methods: This retrospective study aimed to analyse the estimated prevalence of pathogenic/likely pathogenic germline variants in Estonian colorectal cancer patients using NGS in a routine clinical setting. We gathered five-year data (July 2016-July 2021) of colorectal cancer patients (mostly not selected for age or family history) tested with either Illumina TruSight Cancer (94 genes) or TruSight Hereditary Cancer (113 genes) NGS panels. Results: Three hundred and fourteen NGS analyses were performed due to either CRC or polyposis in anamnesis and/or family anamnesis, including 126 CRC cases and 44 colorectal polyposis cases, while 144 were either healthy family members or had other types of cancers. While a known disease-causing variant was identified in 16.4% of all cancer patients tested, we found that 21.4% of CRC patients had such a variant. Among the 44 colorectal polyps cases MLH1, gene was the most affected one (25%), the second and third most affected genes were MSH2 and CHEK2 . Other genes with disease-causing variants found in CRC patients included APC, BLM, BMPR1A, BRCA1, FANCM, MSH6, MUTYH, PMS2, SMAD4, SPINK1 and VHL. Conclusion: Our result give an overview of genetic testing of CRC patients, the prevalence of disease-causing variants and their landscape in Estonia. According to Estonian data, only 2.7-6.1% of CRC patients are genetically tested, which is around ten times less frequently than breast cancer patients and their family members. The diagnostic yield of CRC patients is 21.4%, suggesting that genetic testing will likely improve timely diagnosis and outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roht, Tooming, Rekker, Roomere, Toome, Murumets, Šamarina, Õunap and Kahre.)

Although hereditary breast cancer screening and management are well accepted and established in clinical settings, these efforts result in the detection of only a fraction of genetic predisposition at the population level. Here, we describe our experience from a national pilot study (2018-2021) in which 180 female participants of Estonian biobank (of >150,000 participants in total) were re-contacted to discuss personalized clinical prevention measures based on their genetic predisposition defined by 11 breast cancer-related genes. Our results show that genetic risk variants are relatively common in the average-risk Estonian population. Seventy-five percent of breast cancer cases in at-risk subjects occurred before the age of 50 years. Only one-third of subjects would have been eligible for clinical screening according to the current criteria. The participants perceived the receipt of genetic risk information as valuable. Fluent cooperation of project teams supported by state-of-art data management, quality control, and secure transfer can enable the integration of research results to everyday medical practice in a highly efficient, timely, and well-accepted manner. The positive experience in this genotype-first breast cancer study confirms the value of using existing basic genomic data from population biobanks for precise prevention., Competing Interests: PP was employed by the company Antegenes The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jürgens, Roht, Leitsalu, Nõukas, Palover, Nikopensius, Reigo, Kals, Kallak, Kütner, Budrikas, Kuusk, Valvere, Laidre, Toome, Rekker, Tooming, Ülle Murumets, Kahre, Kruuv-Käo, Õunap, Padrik, Metspalu, Esko, Fischer and Tõnisson.)

Objective: To explore how well physicians who treat hypertension know the indications and contraindications for particular antihypertensive therapies, and how closely their opinions and practice of hypertension treatment agree with national guidelines., Methods: We surveyed by mail a stratified random sample of 10,000 US cardiologists, internists, and general/family practitioners. This survey explored their knowledge, attitudes, and practices with respect to the treatment of hypertension. Responses were compared with national guidelines and product labeling at the time of the survey. Results were stratified by physician specialty., Results: A total of 1,023 physicians, or 10.2% of the sample, responded to the survey. Only 37.3% answered all four knowledge questions correctly, including 25.7% of general/family practitioners, 38.3% of internists, and 49.5% of cardiologists (p < 0.001). In their attitudes with respect to evaluating high blood pressure and establishing treatment goals, most respondents agreed with established guidelines. However, when asked how they would treat uncomplicated, mild hypertension, only 23% limited their selection to diuretics and beta-blockers in accordance with the guidelines. Cardiologists in particular were more likely than internists or general/family practitioners to choose other drug classes, such as angiotensin-converting enzyme Inhibitors or calcium-channel blockers., Conclusions: The results of our survey suggest that national efforts to educate physicians about the increasingly complex armamentarium for hypertension, and to persuade them to base their prescribing on the results of randomized, controlled trials of primary prevention, must be continued.

A survey assessing the practice of epidemiology in the pharmaceutical industry was sent to all member companies and research affiliates of the Pharmaceutical Research and Manufacturers of America (PhRMA) and to six non-member companies. Eighty-three companies were surveyed. Screening questions established whether or not a company employed epidemiologists, had an epidemiology department, or contracted work to epidemiologists outside the company. The survey included questions about organizational structure, functional role of epidemiologists, epidemiology department activities within the company, and collaboration with external partners. The response rate was 90.4%. Of the responding companies, 40% employed epidemiologists, 20% had epidemiology departments, and 36% utilized epidemiologists contracted outside the company. Eighty per cent of companies that employed epidemiologists also contracted epidemiology services outside of the company, while 6.7% of companies that did not employ epidemiologists utilized outside epidemiology services. Among all companies 42.7% employed or utilized epidemiologists. Differences were found in the extent to which large, medium and small pharmaceutical companies employ and utilize epidemiologists. The survey demonstrates that epidemiologists perform many roles within the pharmaceutical industry; that there are many potential opportunities for epidemiologists in this industry and that increased emphasis on safety will require more epidemiology training and recruitment efforts. Copyright (c) 2000 John Wiley & Sons, Ltd.

Purpose: While hypertension treatment is aimed at reducing cardiovascular disease (CVD) risk, there are reports of association between calcium channel blockers (CCB) use and increased risk. However, these studies may be misleading if CCBs are used selectively in high-risk patients., Methods: We conducted a knowledge, attitudes, and practice (KAP) survey by mail of a stratified random sample of 10,000 US cardiologists, internists, and family/general practitioners. Completed surveys were received from 1023 physicians, and population means and frequencies (+/-standard errors) were estimated, Results: While only 36.3 (+/-0.6)% of physicians use long-acting CCBs for mild hypertension without additional risk factors, use increases with moderate or severe hypertension and other risk factors, including history of myocardial infarction (48.4 (+/-0.6)%), family history of CVD (54.6 (+/-0.6)%), diabetes (57.3 (+/-0.6)%), and angina (63.8 (+/-0.5)%). Physicians use CCBs as initial therapy for 24.8 (+/-0.3)% of mildly and 33.1 (+/-0.3)% of moderately hypertensive patients, and add CCBs to the regimens of 39.0 (+/-0.3)% of moderately hypertensive patients not controlled on other antihypertensive therapy. In multiple regression analysis, the proportion of hypertensive patients treated with CCBs was significantly elevated among geriatricians and physicians who believe severity of hypertension is an indication for their use., Conclusion: These findings suggest that CCBs are used selectively for high-risk hypertensive patients. Copyright (c) 2000 John Wiley & Sons, Ltd.

Purpose: Studies of the incidence of epilepsy are limited to a few populations in which new cases can be ascertained. Health maintenance organization (HmO) populations were studied to determine the incidence in a multiethnic, urban United States population., Methods: Cases of initial unprovoked seizure disorder or epilepsy while enrolled in an HMO between 1988 and 1994 were ascertained. Ethnicity was obtained from the medical records and was part of a nested case-control study., Results: There were 197 incidence cases of epilepsy and 275 of initial unprovoked seizure diagnosis. The incidence rate in the age range 0-64 years was 35.5 per 100,000 for epilepsy and 50.9 for initial unprovoked seizure. When compared with population-based studies, rates were slightly higher in children younger than 15, similar for the 15- to 24-year age group, but lower for ages 25-64 years. The ethnicity-specific odds ratios for initial unprovoked seizure, by using non-Hispanic white as the referent, were 1.04 (0.73-1.49) for African-American, 0.97 (0.64-1.48) for Hispanic, and 0.25 (0.08-0.84) for Asian-American., Conclusions: The lower rate in the HMO population is presumably due to a healthy-worker effect. The ethnicity-specific incidence rates do not differ in this population.

The causes of death in Minamata disease were analyzed and compared with those of control subjects. Of the 1422 Minamata disease patients in the Kumamoto Prefecture, 378 had died by the end of 1980. Of these 378, the first death occurred in 1954 with a peak incidence in 1956 when Minamata disease was officially reported for the first time. The number of deaths increased rapidly after 1972 with a second peak in 1976. The male:female ratio was 1.8:1 and the mean age-at-death was 67.2 years (SD = +/- 18.65). The mean age-at-death was younger in the cases of the initial outbreak than in those recently. There were, on the average, 2.8 causes of death per person. Of these cases, 157 (41.5%) had Minamata disease indicated on the death certificate, though 64 (16.9%) had Minamata disease coded as the underlying cause. Minamata disease and the noninflammatory diseases of the central nervous system (CNS) were the main underlying causes of death between 1954 and 1969, while, in the multiple cause data, pneumonia and non-ischemic heart disease were the most prevalent. Cerebrovascular diseases (18.0%) were the main underlying causes of death followed by malignant neoplasms (14.7%), cardiovascular diseases (14.1%) and Minamata disease (14.1%) in 1970 or later, while cardiovascular diseases (18.6%), Minamata disease (14.5%), cerebrovascular diseases (10.4%) and malignant neoplasms (7.1%) were the major multiple causes of death. As compared with the control, the proportions of deaths due to noninflammatory diseases of CNS and pneumonia were higher in the initial outbreak. Although the difference in the causes of death was less apparent recently, malignant neoplasms and hypertensive diseases tended to be lower. These results suggest that there is a need for a long-term follow-up of Minamata disease patients. The data also show the potential value of multiple causes of death coding in analyses of mortality.

Analysis of mortality of 439 deaths that occurred among 1483 patients with Minamata disease (MD) in Kumamoto Prefecture, Japan was performed from the end of 1981. Causes of death and survival rates were studied by means of the standardized mortality ratio (SMR) and life-table technique. Of the 439 deaths (29.6%) in MD cases, the first death occurred in 1954. There was a first peak incidence in 1956 when MD was initially reported, however, the majority of deaths occurred after 1972 when a second and much larger peak was evident. In 1970 an important milestone occurred when the Public Nuisance Relief Law (an anti-pollution law) was enacted. Among its provisions, this law required and enabled verification of MD among people suspected of having been exposed. In contrast to the early cases, later cases of MD were older and their mean age-at-death was not different from that of the general population. The mortality rate for all causes of death was significantly higher in both sexes compared to the general population. Significantly lower survival rates were noted for older patients. The cause-specific mortality rates also showed significantly increased SMRs for liver diseases and nephritis-nephrosis-nephrotic syndrome in male patients, and for nephritis-nephrosis-nephrotic syndrome and other diseases in females. On the other hand, the SMR for senility without mention of psychosis was significantly lower than expected in both sexes.

A study of the distribution and prevalence of bone demineralization in the US population is reported. Based on the HANES I Survey data that incorporated bone density examination of V-2 by the Goldsmith and Vose techniques in a national sample of 6030 adults, it was observed that (1) age-adjusted bone density differences between sexes were consistently found when controlling for race (the prevalence of low bone density was greater among females than males) and (2) whites of both sexes had higher prevalence of low density than blacks in most age-sex categories.

A mail survey was conducted among 3,222 Japanese women 20 to 44 years of age to determine and compare the characteristics of menstruation among women with and without a history of induced abortion. Women with prior abortion consistently reported an excess of symptoms in all age groups. While it is not yet known whether induced abortion results in a physiologic change in the uterus, it is suggested that a psychic component may be present by which women with prior abortion perceive their menses differently than nonabortion respondents.

Low-back pain is a major occupational health problem. Risk factors predisposing to the development of low-back pain are discussed. These include individual risk factors such as age, sex, anthropometry, musculoskeletal abnormalities, muscle strength and physical fitness, psychological factors, and previous attacks of low-back pain and workplace factors such as heavy work, lifting, bending, and slipping. Various programs for prevention are evaluated. These include selection of workers, education and training regarding lifting methods, design of lifting jobs, and fitness training. Limitations of the various studies of these programs are discussed. Preemployment strength testing and ergonomic job design together appear to offer the greatest promise.