Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA.

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with 'damaging' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Sociodemographic factors and strategies in colorectal cancer screening: a narrative review and practical recommendations.

Background: Worldwide colorectal cancer is a frequently occurring cancer with a high disease burden. It is the second most frequent cancer in women and the third in men. The incidence of colorectal cancer is increasing because of ageing and unhealthy lifestyles.Aim: We aimed to perform a narrative literature review on methods and strategies for screening for colorectal cancer prior to colonoscopy.Design: Narrative literature review.Methods: The databases PubMed, Web of Science, Embase and The Cochrane Library were searched using keywords: 'colorectal cancer', '(mass) screening', 'occult blood', 'prevention', 'socioeconomic status', 'early diagnosis', 'Europe' and 'ethnicity'/'ethnic groups'.Results: 18 articles were included. Multiple randomised controlled trials have shown that screening programmes with faecal occult blood tests (FOBT), guaiac-FOBT (gFOBT) and immunochemical FOBT (iFOBT) represent a valid prevention strategy. Most studies favour iFOBT, because of ease to use, resulting in a higher uptake of screening, as well as a higher detection rate. A higher uptake is also achieved by mailing of the test. Overall the uptake of screening is higher in women, although more cancers are diagnosed in men. This can be explained by a lower sensitivity of FOBT in women. Furthermore, a strong correlation was found between a low socio-economic status and a low uptake of screening. The screening age lies between 50-74 years.Conclusion: Colorectal cancer is characterized by a significant incidence, morbidity and mortality. Systematic screening is effective for early detection. A non-selective test with iFOBT currently has the best validity with a higher sensitivity in men.