Patterns of Inheritance: Mendelian and Non-Mendelian
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
An autosomal dominant condition can also be due to a new mutation or an alteration in the genetic code that disrupts the function of the gene in the sperm or egg which produces a child with an autosomal dominant condition. In this situation, neither parent is affected with the condition and there is no history of affected family members. Once the mutated gene is passed to the offspring, then there will be a 50% risk for the autosomal dominant condition to be passed to the next generation. In some autosomal dominant conditions (e.g., neurofibromatosis, achondroplasia), there is a high probability (e.g., 90% for achondroplasia) of an affected offspring born to unaffected parents due to a new or de novo mutation. There is a correlation with older paternal age and de novo mutations for autosomal dominant conditions to occur in their children.
Preconceptional Counseling
Steven R. Bayer, Michael M. Alper, Alan S. Penzias in The Boston IVF Handbook of Infertility, 2017
There is evidence that advanced paternal age can also pose a risk to the fetus. The increased incidence is not based on chromosomal abnormalities, but in the transmission of new genetic mutations. In contrast to oogenesis, spermatogenesis is an ongoing process that continues throughout a man’s life beginning at puberty. The increased frequency of divisions within the spermatocytes increases the chance of errors that can result in a new mutation. These new mutations can result in the passage of an autosomal dominant disorder to an offspring or an X-linked recessive disorder to a grandson, which is called the “grandfather effect.” The incidence of the inheritance of an autosomal dominant condition is 1 in 5000–10,000 deliveries. While the paternal age effect on the occurrence of any specific autosomal dominant condition may be low, the combined effect on all autosomal dominant conditions can be significant. While advanced paternal age increases the risk of these new mutations, testing for all of these autosomal dominant and X-linked disorders is not possible. Further, there is no consensus as to the definition of advanced paternal age. It has been estimated that one-third of new autosomal dominant mutations are the result of advanced paternal age (>40). It seems prudent to suggest that men complete their families by age 40. Even though there is no easy way to screen for all of these genetic conditions in utero, at the very least, couples should be made aware of the potential risk and given the opportunity to meet with a genetic counselor.
Prenatal diagnosis
Louise C Kenny, Jenny E Myers in Obstetrics, 2017
Certain autosomal dominant single gene disorders can now be diagnosed. The test can be offered when the father is known to be affected by the condition, when there is risk of recurrence or where the condition is suspected on ultrasound scan; for example, the autosomal dominant severe skeletal dysplasias such as achondroplasia and thanatophoric dysplasia that are caused by a mutation in the fibroblast growth factor 3 receptor gene (FGFR3). Ultrasound findings such as short long bones (<3rd centile), a small narrow chest with normal head and abdominal measurements can indicate an affected fetus. If the mother is unaffected she will have a normal FGFR3 gene. Where a PCR test on the cell-free DNA in the mother’s blood identifies a mutation in the FGFR3 gene, this must have come from the fetus indicating that the fetus is affected. If the PCR test is negative for the FGFR3 mutation the fetus is unaffected. Since an invasive prenatal diagnostic test is not necessary to make the diagnosis, it can be avoided.
Epidemiology and economic burden of Huntington’s disease: a Canadian provincial public health system perspective
Published in Journal of Medical Economics, 2022
Eileen Shaw, Michelle Mayer, Paul Ekwaru, Suzanne McMullen, Erin Graves, Jennifer W. Wu, Nathalie Budd, Bridget Maturi, Tara Cowling, Tiago A. Mestre
Huntington’s disease (HD) is a rare neurological disorder with autosomal dominant inheritance, with typical onset between 30 and 50 years of age1,2. HD has an estimated disease prevalence of 4.0–13.9 individuals per 100,000 in the general population in Canada and up to 17.2 per 100,000 in the Caucasian population specifically, using data primarily collected in the province of British Columbia3–5. Estimates extrapolated from Fisher and Hayden3 suggest that there are up to 4,700 individuals affected with HD and 14,000 at 50% risk for HD in Canada. Current evidence suggests that the prevalence of HD may be increasing, both in Canada and globally3,5, which may be due to a combination of factors including: improved disease-specific knowledge, greater availability of genetic testing, diminished stigma around HD diagnosis5, expanding cytosine, adenine, and guanine repeats over time6, increasing mutation rates, increasing population life expectancy, and greater availability of symptomatic HD treatments (e.g. anti-choreiform, antidepressant medications)5.
Perceptions of the impact of chorea on health-related quality of life in Huntington disease (HD): A qualitative analysis of individuals across the HD spectrum, family members, and clinicians
Published in Neuropsychological Rehabilitation, 2020
Carey Wexler Sherman, Ravi Iyer, Victor Abler, Alexandria Antonelli, Noelle E. Carlozzi
Huntington disease (HD) is an autosomal dominant neurodegenerative disease that is characterized by motor, cognitive and behavioural deficits. Given the insidious and progressive nature of HD symptoms and associated functional impairments, it is not surprising that this progressive decline and associated symptoms can have a profound impact on health-related quality of life (HRQOL; i.e., mental, social, and physical well-being; Carlozzi et al., 2017; Carlozzi & Tulsky, 2013; Carlozzi, Hahn, Goodnight, et al., 2018; Cella, 1995; Dorey et al., 2016; Fritz et al., 2018; Helder, Kaptein, van Kempen, van Houwelingen, & Roos, 2001; Ho et al., 2004; Ho & Hocaoglu, 2011; Ho, Gilbert, Mason, Goodman, & Barker, 2009; Kaptein et al., 2007; Lai et al., 2018; Paulsen et al., 2013; Read et al., 2013; Ready, Mathews, Leserman, & Paulsen, 2008; Thorley et al., 2018; van Walsem, Howe, Ruud, Frich, & Andelic, 2017; Victorson et al., 2014; Zielonka et al., 2018). For example, chorea, the hallmark symptom of HD, can have a profound impact on both physical l (e.g., injuries and falls; Grimbergen et al., 2008; Jankovic & Roos, 2014) and social well-being (e.g., chorea is often stigmatizing as they are commonly mistaken for drunkenness; Wexler, 2010).
Gorlin syndrome presenting with primary infertility and bilateral calcified ovarian fibromas
Published in Journal of Obstetrics and Gynaecology, 2019
Rashmi Bagga, Shivani Garg, Tanuja Muthyala, Jasvinder Kalra, Pradip Kumar Saha, Aashima Arora, Rimpy Singla, Tulika Singh, Nalini Gupta
A spontaneous pregnancy was reported in a 31-year-old woman with GS and malignant basal naevi of the face, back and chest treated with liquid nitrogen. At 17 weeks of gestation, she underwent a laparotomy and resection of bilateral virilising and renin–prorenin secreting ovarian tumours. She had intra-operative severe hypertension and tachycardia, possibly due to the release of rennin and prorenin during tumour manipulation. She had a preterm delivery at 27 weeks of gestation of a baby boy, who was also affected with GS (Yoshizumi et al. 1990). Another factor to be considered is the 50% chance of inheritance of this autosomal dominant syndrome in the offspring. A prenatal diagnosis by chorionic villus sampling or amniocentesis may be made if a specific mutation is identified. Mid-trimester sonography detects bony or cranial malformations in an affected foetus (Chen et al. 2006).