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Genetics and metabolic disorders
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
Achondroplasia is autosomal dominant (80% of cases represent new mutations). The risk to the offspring of an affected person will be 1 in 2 for each pregnancy. Consanguinity does not increase the risk in offspring unless both parents are affected. If both parents have achondroplasia, there is a 1 in 4 chance that an offspring will be unaffected. Complete penetrance implies that those who do not show the phenotype do not carry the mutation and therefore cannot pass it on. The gene responsible for the disorder has recently been identified as the fibroblast growth factor receptor-3 (FGFR-3), with almost all affected individuals carrying the same mutation. Prenatal diagnosis is now possible by DNA analysis.
Familial Atypical Multiple Mole Melanoma Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
FAMMM follows an autosomal dominant inheritance pattern (Figure 39.1c) with variable penetrance and expressivity [1,15,23,24]. Penetrance is affected by a number of genetic and environmental factors (see Section 39.4 for details). While hereditary melanoma has been associated with SNPs and mutations in a variety of genes, FAMMM is most closely associated with a mutation in the gene CDKN2A and occasionally CDK4. In fact, hereditary melanoma accompanied by dysplastic nevi indicates the likelihood of a CDKN2A mutation [1].
Genetics
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Jane A. Hurst, Richard H. Scott
Children (and adults) with AD conditions have a mutation on one the two alleles of the gene (‘monoallelic’ or heterozygous mutation). Aspects of inheritance in AD disorders include: Differences in expression with inter- and intrafamilial variability.Penetrance: the percentage of individuals who have any features of the disorder. This may be age-dependent penetrance or incomplete penetrance (not all mutation carriers will develop the condition).Somatic mosaicism: a new mutation arising at an early stage in embryogenesis may result in a partial or modified phenotype.Germline/gonadal mosaicism: a new mutation arising during oogenesis or spermatogenesis may cause no phenotype in the parent but can be transmitted to the offspring.Paternal age effect: for some AD disorders the chance of a new mutation from the father increases with his age. However, the absolute risk of recurrence following a new mutation remains low.Anticipation: worsening of disease severity in successive generations.
Combined exome analysis and exome depth assessment achieve a high diagnostic yield in an epilepsy case series, revealing significant genomic heterogeneity and novel mechanisms
Published in Expert Review of Molecular Diagnostics, 2023
Danai Veltra, Faidon-Nikolaos Tilemis, Nikolaos M. Marinakis, Maria Svingou, Anastasios Mitrakos, Konstantina Kosma, Irene Tsoutsou, Periklis Makrythanasis, Virginia Theodorou, Marina Katsalouli, Pelagia Vorgia, Georgios Niotakis, Georgios Vartzelis, Argirios Dinopoulos, Athanasios Evangeliou, Stella Mouskou, Anastasia Korona, Sotiria Mastroyianni, Antigone Papavasiliou, Maria Tzetis, Roser Pons, Joanne Traeger-Synodinos, Christalena Sofocleous
Variable and complex modes of inheritance, penetrance, and expressivity should always be considered during interpretation and diagnosis. In families 2, 10, 20, 25, and 28, the familial pathogenic variants, in SCN1A, KCNT1, PCDH19, COL4A2, and IFIH1 genes, respectively, were also detected in asymptomatic parents. Acknowledged incomplete penetrance may explain extreme clinical heterogeneity even within the members of the same family [44–48]. In family 10, the KCNT1 pathogenic variant was detected in three family members presenting with heterogeneous phenotypes including idiopathic generalized epilepsy (IGE) and ASD in the proband and febrile and afebrile seizures in his sister. The third member, the proband’s father, is reported to have parkinsonism but whether this could be related to the KCNT1 variant is unknown. With respect to variable expressivity, CUX2:p.Glu835Argfs*21, a likely pathogenic frameshift variant, was detected in a male patient with GGE and learning difficulties, and also his father who had epilepsy persisting until adulthood (family 58). To the best of our knowledge, only de novo missense variants and especially the recurrent CUX2:p.Glu590Lys variant, have so far been associated with DEE [49] and this is the first report of variable expressivity associated with CUX2 variants.
Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches
Published in Expert Review of Respiratory Medicine, 2022
Auyon J. Ghosh, Brian D. Hobbs
While individuals with AATD all have pathological variants, not all individuals with the pathological variants exhibit AATD-associated lung disease and there is substantial heterogeneity in the effects of the pathological variants on lung function in a given individual [26]. This example of variable penetrance can be observed in the inconsistent clinical outcomes for a given genotype. For example, lung disease associated with AATD has historically been associated with basal-predominant, pan-lobular emphysema in contrast to the apical-predominant, centrilobular emphysema in usual COPD. However, approximately 40% of subjects with AATD and COPD had apical-predominant emphysema [27]. Disease penetrance is further complicated by late-onset lung disease, the variability of lung function measurements, inconsistent exposure to cigarette smoking, and poorly replicable measurement of lung function. In general, individuals with AATD have normal lung function through age 30 though report more respiratory symptoms (even never-smokers) compared to their non-AATD counterparts [28,29]. By age 40, individuals with AATD who are ever-smokers can have decreases in lung function consistent with COPD [30]. However, in family-based and general population genetic studies (such as the UK Biobank), approximately 63% of all AATD individuals and one-third of current or former smoking individuals with severe AATD have normal lung function [21,26].
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
While the disease-causing gene is primarily responsible for the specific disease phenotype, the location and type of mutation in the gene also influence the type and severity of the clinical phenotype [38–40]. However, there are still other factors that determine the clinical presentation. Different individuals with the same mutation of an implicated gene can have different clinical presentations ranging from silent carriers to patients with malignant forms of the disease. This is the concept of variable penetrance, and numerous genetic and non-genetic modifiers can determine it. It has been found that common variants of the aforementioned genes can influence ion channel function, thus causing variability in repolarization and thus variability in the QT interval, not amounting to LQTS. The presence of these common variants side-by-side with disease-causing LQTS mutations results in gene–gene interactions that are responsible for variable penetrance [41,42].