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The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
The same clinical diagnostic consequences arise in other adult-onset autosomal dominant disorders. Most commonly sought for PGT-M are the heritable cardiac conditions Long Q-T syndrome (LGT1, LGT2, LGT8), hypertrophic cardiomyopathy (CMH1, CMH4, CMH8), and dilated cardiomyopathy (Type 1A, 1DD, 1E,1G). In these autosomal dominant disorders, identification typically follows a family member being identified in the context of athletic exertion. Relatives of reproductive age often prefer prenatal genetic diagnosis through PGT-M.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
In autosomal dominant genetic disorders, only one copy of a mutant allele is necessary for expression of the disease (Fig. 16). Thus, heterozygotes will be affected. The risk of passing on the mutation to an offspring is 50% for each pregnancy. Vertical transmission of the disorder is seen on pedigree analysis, and the condition can often be traced back many generations. However, there are certain caveats to keep in mind when evaluating autosomal dominant disorders. First, there is a high degree of variability of expression of dominant conditions. Even within the same family, some individuals may be severely affected while others may have very mild and medically insignificant features. Thus, thorough review of medical histories and physical examinations on multiple family members are often parts of a genetic evaluation. Second, there may be reduced penetrance of a dominant disorder. Thus, a heterozygote may not show any manifestations of the mutant gene after a complete medical evaluation. Finally, many autosomal dominant disorders have a high new spontaneous mutation rate and a dominant condition may appear de novo in an isolated individual in a pedigree. However, once present, it can be passed on to subsequent generations. In general, abnormal genes in autosomal dominant disorders likely encode structural proteins, such as collagen, which is abnormal in osteogenesis imperfecta, or fibrillin, which is mutant in Marfan syndrome.
Thyroid disease
Published in Neeraj Sethi, R. James A. England, Neil de Zoysa, Head, Neck and Thyroid Surgery, 2020
When genetically predetermined, MTC has three forms: multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B) and familial MTC. All are inherited as autosomal dominant disorders. In MEN, the disease is associated with other endocrine disorders (see Table 6.5).
RNA therapeutics for retinal diseases
Published in Expert Opinion on Biological Therapy, 2021
Michael C Gemayel, Ashay D. Bhatwadekar, Thomas Ciulla
The use of shRNA is encouraging, especially in cases of autosomal dominant disorders, namely adRP. Here, gene therapy typically must suppress a mutation causing a toxic gain of function. A promising approach involves a ‘knockdown and replace’ strategy, whereby shRNA targets RHO in a mutation-independent manner and is co-packaged in a single adeno-associated viral vector with an RNAi resistant replacement RHO gene. Efficacy of this technique was shown in pre-clinical canine models demonstrating suppression of endogenous RHO RNA with replacement RHO gene resulting in 30% of the normal protein levels, as well as protection of photoreceptors from retinal degeneration following subretinal vector administration [65]. Iveric Bio is currently attempting to apply this model to humans using mutation-independent gene therapy (IC-100) [66]. Additional studies have shown the ability to silence endogenous VEGF production with anti-VEGF shRNA AAV2/8 vector administered subretinally, demonstrating reduction of choroidal neovascularization in AMD mouse models [67].
The utility of whole exome sequencing in diagnosing neurological disorders in adults from a highly consanguineous population
Published in Journal of Neurogenetics, 2019
Weiyi Mu, Nicoline Schiess, Jennifer L. Orthmann-Murphy, Ayman W. El-Hattab
WES data analysis is known to be of high efficacy when focusing on pathogenic homozygous variants. The overwhelming majority of molecular diagnoses in our cohort were autosomal recessive disorders, and in every case, the mutations were homozygous. Each of these cases was from parents who were second cousins or closer in relation. These findings were in accordance with prior studies in populations with high consanguinity rates, which showed a larger proportion of autosomal recessive disorders among the molecular diagnoses, as expected (Al-Shamsi, Hertecant, Souid, & Al-Jasmi, 2016; Alfares et al., 2017; Charng et al., 2016; Harripaul et al., 2017; Makrythanasis et al., 2014; Reuter et al., 2017). It should be noted however that in our cohort, there were also three cases of autosomal dominant disorders, of which one was determined to be due to a de novo mutation. A next-generation sequencing study involving WES as well as multi-gene panels in the Saudi Arabian population also found a substantial proportion of dominant disorders (Monies et al., 2017). Nonrecessive inheritance patterns should not be excluded as modes of inheritance, despite the preponderance of recessive causes.
What the internist should know about hereditary muscle channelopathies
Published in Acta Clinica Belgica, 2018
Véronique Bissay, Sophie C. H. Van Malderen
In contrast to NDM, DM is associated with progressive muscle weakness (muscular dystrophy) and extra-muscular systemic involvement [2]. Two autosomal dominant disorders are recognized in this category, being Steinert’s disease or DM1, and proximal myotonic myopathie (PROMM) or DM2. DM1 has a prevalence of 1 in 8000. The incidence of DM2 is not well defined. Genetically they result from unstable CTG repeats in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene on chromosome 19q13.3 and the unstable tetranucleotide CCTG repeat expansion in intron 1 of the Zinc finger 9 (ZNF9) gene on chromosome 3q21, respectively [12]. Myotonic features of DM are most likely due to dysfunction of the voltage gated Cl Channel 1 as a result of the alternative CLCN1 gene splicing.