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Bardet−Biedl Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
BBS displays an autosomal recessive inheritance pattern, and involves inheritance of two abnormal variants/alleles (one from each parent) to develop overt disease. An individual who receives one normal allele and one mutated allele is a carrier for the disease and is usually asymptomatic. Two carrier parents have a 25% chance of having an affected child (containing two abnormal/mutated alleles), a 50% chance of having a carrier child (containing one normal allele and one abnormal allele), and a 25% chance of having a normal child (containing two normal alleles). As BBS mutations exert dominant-negative effects on the function of the remaining (wild-type) gene allele, some carriers with heterozygous mutations may sometimes become symptomatic, and others acquire additional mutations in another gene. The inheritance of multiple mutations involving multiple genes in autosomal recessive disorder is known as oligogenic inheritance [18]. A BBS-affected individual who carries two mutations (i.e., homozygous mutations) in one gene and a third mutation (i.e., heterozygous mutation) in a separate gene is defined as showing triallelic inheritance pattern [19].
Human Genetic Variability and Susceptibility to Infectious Diseases
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Tuberculosis, a chronic mycobacterial disease due to M. tuberculosis, affects about one third of the world’s population and causes an estimated 3 million deaths each year (107). As with leprosy, the disease likely results from complex interactions between M. tuberculosis, environmental factors, and host genes. Among the vast number of infected persons, only 10 million people actually develop the disease each year. In humans, the role of genetic factors in tuberculosis was first suggested on the basis of strong ethnic differences, in particular a higher prevalence of the disease among blacks than among whites (108). Twin studies confirmed the importance of host genes by showing differences in concordance rates between monozygotic (~60%) and dizygotic (~20%) twins [reviewed in (75)]. Compared to leprosy, very few familial studies have been performed for tuberculosis. A segregation analysis that was performed recently in Brazil (109) found evidence for a complex genetic model involving oligogenic inheritance. A weak linkage was observed with the NRAMP1 region in this study, but, so far, no definitive results of ongoing genome-wide linkage studies (38) have been reported.
The inherited basis of hypergonadotropic hypogonadism
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Although normosmic CIHH and KS have long been considered as monogenic disorders with a Mendelian inheritance pattern, several cases of possible digenic/oligogenic inheritance in KS44 have been reported. Such digenic inheritance has been shown in both KS and normosmic CIHH patients who bore mutations in both PROKR2 and PROK2, in FGFR1 and NELF, or in GNRHR as well as in PROKR2, and GnRH1, GNRHR, or KISS1R.89 Defects in different genes could act synergistically to induce the CIHH or the KS phenotype, or to modify the severity of the GnRH deficiency, partially explaining the phenotypic variability observed within and across families with CHH and KS.
Identification of rare missense mutations in NOTCH2 and HERC2 associated with familial central precocious puberty via whole-exome sequencing
Published in Gynecological Endocrinology, 2020
Hae Sang Lee, Hwal Rim Jeong, Jung Gi Rho, Chang Dae Kum, Kyung Hee Kim, Do Wan Kim, Jae Youn Cheong, Seon-Yong Jeong, Jin Soon Hwang
The mechanisms by which NOTCH2 and HERC2 mutations result in early activation of the hypothalamus-pituitary axis are still unknown. In this study, patients with CPP in family 1 had missense variants in both NOTCH2 and HERC2; their parents who had either NOTCH2 or HERC2 coding variants exhibited no phenotype of CPP. We hypothesize that the two mutations may have synergistic actions to affect the same ligand/receptor pair or signaling pathway. CPP, though characterized by a strong genetic component, is a complex and multifactorial disorder. CPP can occur as a result of monogenic mutations such as in MKRN3 or KISS1, but the frequency of monogenic CPP is relatively low. The genetic regulation of pubertal onset most likely results from the additive effects of multiple genes. Indeed, digenic or oligogenic inheritance has been described as a possible pathogenic explanation for this disease. Therefore, digenic inheritance of the NOTCH2 and HERC2 variants revealed in our study may be associated with the development of CPP through the Notch signaling pathway, but this requires further evidence or needs to be replicated.
Congenital fibrinogen disorder caused by digenic mutations of the FGA and FGB genes
Published in Hematology, 2020
Xiong Wang, Ning Tang, Na Shen, Yanjun Lu, Dengju Li
For some disorders, the discovery of rare genetic variants and the observation of familial co-segregation in some cases result in the perception that Mendelian inheritance may apply. However, recent advances in genetic tests have revealed several disorders beyond the One Gene-One Disease paradigm, indicatinga more complex inheritance and pleiotropy in heritable disorders [13]. Cerrone et al., reported that oligogenic or polygenic genetic variants contributed to inheritable cardiac disorders [14]. Monogenic, polygenic, and oligogenic inheritance were found in familial hypercholesterolemia [15]. In polygenic or oligogenic inheritance, one variant may function as genetic modifiers determining the ultimate disease manifestations. Kuuluvainen et al., reported that the penetrance of SOD1 p.Ala90Val mutation was modulated by other variants, indicating oligogenic basis of sporadic ALS [16]. Within bleeding, thrombotic and platelet disorders, Downes et al., reported 3.9% and 1.8% patients harbored oligogenic variants for the thrombotic and coagulation classes in a large cohort in UK recently [17]. This is the first time we have identified oligogenic mutations of the FGA and FGB genes for CFD in Chinese.
Advances in the understanding of hereditary ataxia – implications for future patients
Published in Expert Opinion on Orphan Drugs, 2018
Anna Zeitlberger, Heather Ging, Suran Nethisinghe, Paola Giunti
The success of NGS in a research setting is outlined by its role in the discovery of several new ataxia associated genes, including TGM6 (SCA36) [29], CACNA1G (SCA42) [109], ATP2B3 (X-linked congenital cerebellar ataxia) [110], PNKP (ataxia with oculomotor apraxia type 4) [111], ABCB7 (X-linked congenital cerebellar ataxia) [112], KCND3 (SCA19/22) [113], and TPP1 (SCAR7). Some of these genes have previously been described in the context of other neurological and non-neurological diseases, such as ceroid lipofuscinosis (TPP1) and Brugada syndrome type 9 (KCND3). Mechanism of genetic pleiotropy includes different downstream effects of mutations within the same gene, modifier genes, and oligogenic inheritance [114]. The best known example of genetic pleiotropy within the group of ataxias is CACNA1A mutations that can present as SCA6, episodic ataxia type II and familial hemiplegic migraine due to different functional downstream mechanisms [115].