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Genetic Counseling in Assisted Reproductive Technology
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Autosomal dominant inheritance is when mutation in one allele of an autosomal gene is sufficient to cause disease. An affected individual typically has one non-functional allele and one functional allele. Either allele can be passed on to subsequent generations, resulting in a 50% recurrence risk for each offspring. Dominant conditions can sometimes be seen in a family, passed down from generation to generation and shared among siblings. Sometimes, dominant conditions are caused by a de novo gene change, when an individual can be the first in the family to be affected.
Genetic Disorders
Published in Jeremy R. Jass, Understanding Pathology, 2020
Autosomal dominant conditions are passed from parent to child with each child having a 50% chance of inheriting the altered gene. Such conditions are therefore easy to recognise, particularly because they are often associated with obvious physical and/or mental changes. Pathologists have generally contributed to the recognition of autosomal dominant conditions associated with internal abnormalities such as neoplasia. This has come about either through autopsy practice, in which connections have been made between multiple and apparently unrelated lesions, and/or through the pathologist’s traditional interest in cancer.
Genomics and Hearing Loss: Toward a New Standard of Care?
Published in Stavros Hatzopoulos, Andrea Ciorba, Mark Krumm, Advances in Audiology and Hearing Science, 2020
The autosomal dominant inheritance refers to a trait or disorder in which the associated phenotype can be expressed in individuals who have only one copy of a pathogenic variant at a particular locus. The individual is said to be heterozygous for the trait. This pattern specifically refers to a gene located on one of the 22 pairs of autosomes, that is, a nonsex chromosome. For a given type of hearing loss, if individuals in each generation are affected and both males and females are equally affected, the pattern of inheritance is probably autosomal dominant. Also, all affected individuals will have at least one parent who carries the disease allele unless a new mutation has occurred.
Histopathology of the Conduction System in Long QT Syndrome
Published in Fetal and Pediatric Pathology, 2022
Alexandra Rogers, Rachel Taylor, Janet Poulik, Bahig M. Shehata
There has also been evidence suggesting that JLNS could be inherited in an autosomal dominant fashion. This was demonstrated by Sanyal et al., who spent 16 years tracking the inheritance of JLNS in a family of 66 blood relatives. Results demonstrated that in families where one parent was diagnosed with JLNS, nearly 70% of offspring were also affected. Comparatively, in families where neither parent was afflicted, 0% of offspring had JLNS [7]. The significantly increased rate of successive generational affliction suggests an autosomal dominant inheritance. These findings were corroborated by Splawski et al. who postulated an autosomal dominant mode of inheritance for JLNS with an autosomal recessive inheritance pattern for the associated sensorineural deafness [7]. Several other studies have also confirmed these data, however, no final consensus has been reached regarding the mode of inheritance of JLNS.
Torpedo-like lesions in the ocular fundi of Gardner syndrome: hiding in plain view
Published in Ophthalmic Genetics, 2021
Kirk Packo, Morton F. Goldberg
The APC gene (Adenomatous Polyposis Coli), located on chromosome 5, is noteworthy for its approximately 700 mutations spread along its length like a string of pearls. Their varied clinical abnormalities include the following: supernumerary teeth, cranial osteomas, epidermal cysts, intestinal polyposis, brain and other tumors (both benign and malignant), as well as a variety of pigmentary abnormalities in the fundus. Each of these abnormalities in Gardner syndrome/FAP can be inherited singly or in combination, or, importantly, not at all. Variability in appearance is typical, depending on how many (and which) exons harbor the different mutations. For example, Olschwang et al. (48) showed that varied extracolonic manifestations of the FAP syndrome are correlated with specific mutations in the APC gene; and, as noted by Alberge et al. (47), the RPE lesions in FAP are due to varied APC mutations between codons 541 and 1309. Additionally, the number of colonic polyps is correlated with different but specific mutations in the APC gene. When the number of polyps is small, the different clinical phenotype is separately named “Attenuated FAP”. In summary, the clinical appearance of affected individuals depends on the highly varied pleiotropic expressions of the abnormal gene in individual patients. Such varied clinical expressions are frequently observed in autosomal dominant diseases.
First-trimester detection of micrognathia as a presentation of mandibulofacial dysostosis with microcephaly
Published in Journal of Obstetrics and Gynaecology, 2021
Bi-Qiu Xu, Li Zhen, Dong-Zhi Li
EFTUD2 encodes a small GTPase that is one of several subunits belonging to the U5 small nuclear ribonucleoprotein particle (snRNP) (Fabrizio et al. 1997). The U5 snRNP is a component of the major and minor spliceosome, two large macromolecular machines that mediate intron splicing. Therefore, a shortage of this enzyme impairs mRNA processing. This condition is inherited in an autosomal dominant pattern, and almost all cases result from new variants in the gene and occur in patients with no history of the disorder in their family. A range of gene deletions and rearrangements, as well as pathogenic point mutations of EFTUD2, have been reported. According to ACMG 2015 guidelines (Richards et al. 2015), the c.1058 + 1G > A variant is classified as likely pathogenic. A similar donor splice site variant, c.1058 + 2dup, has been reported in a MFDM patient (Yu et al. 2018). In total, splice site variants account for 29% of cases of MFDM. These arguments support the hypothesis that c.1058 + 1G > A is the causative variant in the present case. Although WES discloses the EFTUD2 variant in many sporadic cases, this approach is not recommended as a first-tier testing due to its technology limitations in the detection of gene deletions, which makes up approximately 16% of all reported MFDM-associated EFTUD2 defects (Gandomi et al. 2015; Zarate et al. 2015). WES is an excellent second-tier/reflex testing option in prenatal cases with structural anomalies when pathogenic copy number variations have been ruled out.