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Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
In multifactorial inheritance, it is postulated that genetic influences from both parents, in combination with environmental factors, lead to a specific birth defect or disorder. In polygenic inheritance, multiple genetic influences in combination act together to produce a disorder. Examples of birth defects with multifactorial inheritance include isolated congenital heart defects, cleft lip with or without cleft palate, cleft palate, neural tube defects, pyloric stenosis, and congenital dislocation of the hips (Table 4). In multifactorial disorders, there is no evidence to suggest simple Mendelian inheritance. For example, the defect does not necessarily appear in sequential generations of a family, as would an autosomal dominant condition due to a single-gene mutation. However, there may be clustering of the defect in more than one member of a pedigree. The appearance of multifactorial disorders has been explained by a threshold model in which certain genes present in an individual, along with prenatal environmental factors, accumulate toward a threshold. If an individual has enough of these genes and factors, a threshold will be crossed and the defect will appear (32).
Genetics and metabolic disorders
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
3.22. In multifactorial inheritance, factors affecting the risk to relatives arethe presence of multiple affected family members.the age of the parent at the time of proband's birth.closeness of the relationship to the proband.the presence of severe and/or early onset disease in the proband.whether or not the proband is shown to have a normal karyotype.
Understanding genetics and genetic tests
Published in David M. Luesley, Mark D. Kilby, Obstetrics & Gynaecology, 2016
Most conditions seen by healthcare professionals are multifactorial. In multifactorial inheritance, a condition occurs as the result of a combination of environmental factors such as obesity or smoking, and numerous genetic factors. More rarely a condition occurs because of an alteration to the number or structure of a chromosome, or a mutation in an individual gene. It is important that these ‘chromosomal’ and ‘single-gene’ disorders are recognised as they may have significant implications to the wider family. Mitochondrial disorders always show maternal inheritance and, as they are rare, will not be discussed further. Disorders due to somatic mutations are unlikely to be encountered in obstetric practice, but are extremely common and play an important role in the development of many cancers. A few conditions may be the result of environmental factors alone, e.g. fetal anticonvulsant syndrome. These environmental conditions are also not discussed here.
Current advances in the management of cluster headaches
Published in Expert Opinion on Pharmacotherapy, 2021
Theodoros Mavridis, Marianthi Breza, Christina Deligianni, Dimos D. Mitsikostas
To date, many epidemiological studies have shown that there is an increased risk of CH in relatives of patients with CH. A recent systematic review and meta-analysis estimates a rate of family history in CH to be approximately 6.27% (95% CI: 4.65–8.40%) [5]. The possible inheritance pattern has not yet been elucidated, and various studies suggest either an autosomal recessive, an autosomal dominant or a multifactorial inheritance pattern [6,7]. Many genes (e.g. CACNA1A, HCRTR2, PER1, PER3) were meticulously investigated in family studies, with no conclusive results so far [4]. Candidate susceptibility genes were identified in CH genetic studies, including hypocretin/orexin receptor type 2 (HCRTR2), alcohol dehydrogenase 4 (ADH4), G protein beta3 (GNB3), pituitary adenylate cyclase-activating polypeptide type I receptor (ADCYAP1R1, encoding for PACAP receptor) and membrane metallo-endopeptidase (MME) genes [8]. More specifically, HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms were associated with susceptibility to CH. Furthermore, alleles of GNB3 rs5443 polymorphism were found to be related to triptan response in particular populations [9], highlighting thus the importance of pharmacogenomics, indicating that the management of CH may significantly rely on specific genetic factors. Further studies are needed, however, to understand the role of genetics in the pathophysiology of CH.
Strict network analysis of evolutionary conserved and brain-expressed genes reveals new putative candidates implicated in Intellectual Disability and in Global Development Delay
Published in The World Journal of Biological Psychiatry, 2021
Rafael Mina Piergiorge, Ana Tereza Ribeiro de Vasconcelos, Márcia Mattos Gonçalves Pimentel, Cíntia Barros Santos-Rebouças
The significant molecular sub-diagnosis rate of ID/GDD, even considering high throughput sequencing approaches, can be justified by four essential issues. First, the consensus that several genes (coding and non-coding) individually or mutually associated with these entities remains to be elucidated. Moreover, many causal variants are still missed, either because they are located in non-captured regions or they are captured, but their genomic architecture does not allow an adequate variant calling by using the existing pipelines (ex complex indels, repetitive regions, segmental duplications, pseudogenes). Moreover, some causal variants could have a more complex genetic landscape (oligogenic/multifactorial inheritance mode or incomplete penetrance). Finally, the discovery of a rare potential causal variant in a gene never associated before with the condition marks the beginning of a research effort to validate the finding, not being considered a diagnostic result. The fact that the expression of many genes related to cognitive function is restricted to the central nervous system (CNS) or includes other inaccessible tissues limits further functional validation in living patients. Besides the genetic gap underlying ID/GDD, it is worth mentioning that during variant prioritisation in massive sequencing pipelines, there is not a normative for the genes that should be evaluated, with numbers widely varying among institutions and different platforms (Srivastava and Schwartz 2014; Piñero et al. 2015; Vissers et al. 2016; Koscielny et al. 2017; Jamra 2018; Neri et al. 2018).
Association of Activity Altering Genotypes - Tyr113His and His139Arg in Microsomal Epoxide Hydrolase Enzyme with Esophageal Squamous Cell Carcinoma
Published in Nutrition and Cancer, 2019
Sumaiya Nabi, Gulzar Ahmad Bhat, Beenish Iqbal, Mohd Maqbool Lone, Ghulam Nabi Lone, Maroof Ahmad Khan, Nazir Ahmad Dar
Family history, as a proxy of genetic and shared environmental risk factors substantially elevated the ESCC risk in high incidence areas of ESCC and the magnitude of the risk further increased when first degree relatives were affected or when same organ cancer history was reported in their families (59). Family history of a cancer reflects the consequences of genetic susceptibilities, shared environment, and common behaviors (60). Although, in some families, highly penetrant genetic mutations are rarely transmitted through generations, resulting in a high likelihood of disease (61), however, in majority of families, genetic susceptibility is transmitted through many low penetrant genes, for example carcinogen metabolizing genes that interact with environmental factors to increase the risk for disease (62). Hence, testing for polymorphisms in individuals with a family history of disease could further refine risk, as familial clustering of disease typically reflects multifactorial inheritance in which susceptibility is determined by the combined effects of a number of genes interacting with environmental and lifestyle factors (60). In the present study, positive history of cancer in the family independently as well as in presence of exon 3 and exon 4 variant and altered (high or low) mEH activity genotypes increased the risk of ESCC and when tested for interaction, a statistically significant interaction between family history of cancer, altered mEH activity (high or low) and ESCC was found (Pinteraction = 0.018). These findings indicate the inheritance of vulnerable genotypes may contribute to the ESCC risk.