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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
Expansion of the CGG triplet repeat in the FMR1 gene is responsible for fragile X syndrome. Women who carry a premutation in this gene do not have fragile X syndrome but can have a unique set of symptoms associated with a premutation, including primary ovarian insufficiency (POI). Women who carry the full mutation in this gene can have a diagnosis of fragile X syndrome, although, because of skewed X-inactivation and the presence of a fully functioning copy of the FMR1 gene on their other X chromosome, may manifest a milder form of the disease than males who inherit a full mutation. Clinical trials report an incidence of the FMR1 premutation in as many as 14% to 20% of women with familial POI and 2% to 5% of women with sporadic POI (Torrealday et al., 2017).
Population aspects of genetic counselling and genetic screening
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Screening of particular subgroups, rather than of entire populations, may be appropriate for certain genetic disorders. A case can be made for this in screening those with mental handicap for fragile X syndrome, allowing an explanation to be provided for serious difficulties and allowing a high genetic risk to be recognised that may give options for family members to avoid recurrence of the disorder. Clear information and proper consent, with access to fuller genetic counselling, are essential factors that must be built into any such programmes. This requires adequate resourcing. Such screening of symptomatic, affected groups should be carefully distinguished from more general population and prenatal screening.
The Human Genome Project and Its Impact on Understanding Developmental Disabilities
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Daniel J. Wattendorf, Maximilian Muenke
The most common monogenic disorder associated with mental retardation is fragile X syndrome. Pleiotropic somatic and behavioral features include facial dysmorphism with a long narrow face and prominent ears, unusual growth patterns, macroorchidism, developmental delay with mental retardation, hyperactivity, and autistic-like behaviors (55). Caused by a mutated allele of FMR1, fragile X syndrome is transmitted as an X-linked dominant disorder that is due to a trinucleotide repeat (CGG) that expands during meiosis from a premutation size to a full mutation. This increase in size of the CGG-repeat leads to excessive methylation extending from the site of the repeat in the 5′UTR to the adjacent promoter with subsequent loss of expression of its protein, FMRP. While the phenotypic effects are attributed to the absence, and thus, loss of function of FMRP, there may be detrimental effects associated with a premutant allele (i.e., an expanded CGG-repeat, but without methylation induced gene silencing) due to a gain-of-function. For example, premutation females may have premature ovarian failure (56).
A bibliometric analysis of primary ovarian insufficiency from 2010 to 2020
Published in Climacteric, 2022
Z.-H. Deng, H.-J. Tan, L. Wang, P.-P. Long, D. Guo, R.-P. Quan, M.-H. Zeng, H.-W. Deng, H.-M. Xiao
Mutation in the FMR1 gene is associated with Fragile X syndrome, in which patients are more likely to suffer from POI. Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome. Typical clinical manifestations include ovarian dysgenesis, hypogonadotropic hypogonadism and infertility [20]. In addition to cancer patients, fertility preservation techniques may also be used in patients with Turner syndrome and Fragile X syndrome. Unfortunately, most of the data on fertility preservation available in the literature concern cancer patients while patients with syndromic POI present a particular complexity due to other co-presence symptoms. Fertility preservation in these patients should be treated accurately and individually [21].
Therapeutic potential of GABAA receptor subunit expression abnormalities in fragile X syndrome
Published in Expert Review of Precision Medicine and Drug Development, 2022
Mathijs B. van der Lei, R. Frank Kooy
Fragile X syndrome is the most common inherited cause of intellectual disability, with a prevalence of approximately 1 in 4000–7000 males and 1 in 6000–11000 females [1]. The disorder is characterized by mild to severe behavioral alterations, including hyperactivity, attention deficits, anxiety, and autism [1–3]. Typical physical features include prominent ears, long faces and flat feet [1,4,5]. The mutational basis of fragile X syndrome is the abnormal expansion and consequent hypermethylation of a CGG trinucleotide repeat in the promoter region of the fragile X mental retardation 1 (FMR1) gene, leading to transcriptional silencing and absence of fragile X mental retardation protein (FMRP) production if the expansion exceeds 200 CGG repeats. FMRP is an RNA binding protein involved in many cellular processes, including the regulation of RNA transport and decay, protein synthesis and synaptic plasticity [1,6,7]. Current treatment is symptomatic and no specific drugs are available for the disorder yet.
Diagnostic profile of the AmplideX Fragile X Dx and Carrier Screen Kit for diagnosis and screening of fragile X syndrome and other FMR1-related disorders
Published in Expert Review of Molecular Diagnostics, 2021
Elizabeth Berry-Kravis, Lili Zhou, Jonathan Jackson, Flora Tassone
The American College of Medical Genetics and Genomics (ACMG) practice guidelines state that the identification of an FMR1 expansion into the full mutation (FM) range in males supports the diagnosis of Fragile X Syndrome (FXS) due to the very high penetrance of full mutations in males. The severity may be influenced by other factors and cannot be predicted from the size of the full mutation alone. If premutations (PM) are also present (giving arise to size mosaicism), the phenotype may be less severe. Females with FM results may exhibit a wide spectrum of phenotypes from severe to unaffected. Presence of a premutation indicates a risk for FXPOI in females and for FXTAS in both male and female patients. When used for carrier screening, females with PM or FM expansions are at higher risk for offspring with FXS and related syndromes, particularly in male offspring, while males with PM or FM will have female offspring that are carriers.