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Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
Female carriers with the premutation of this FMRP translational regulator 1 gene (55-200 CGG repeats) have an increased risk of premature ovarian failure. Premature ovarian failure is defined as the development of hypergonadotropic hypogonadism prior to age 40. Male carriers of the premutation are at risk of fragile X–associated tremor/ataxia syndrome (FXTAS). This disease may develop in as many as 20%–33% of adult male permutation carriers, with increasing age and length of CGG repeats correlated with greater motor impairment [15]. FXTAS may also occur in female carriers due to X-inactivation.
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).
Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Mutations in the FMR1 gene can affect multiple generations in the same family in different ways. When a mother carrying the premutation allele passes it to her child, the allele may expand to a full mutation allele. This means that if a child is diagnosed with fragile X syndrome, their mother is either a premutation or full-mutation carrier and at risk for FXTAS. Furthermore, the child's grandparents, aunts, uncles, siblings, and cousins are at risk for carrying the premutation and developing FXTAS or having children with fragile X syndrome. Testing of family members should be done in conjunction with a genetic counselor who will review testing options, the probability of having symptoms if the premutation is present, and risk of recurrence with additional pregnancies.
Premature ovarian insufficiency – the need for a genomic map
Published in Climacteric, 2021
Currently, the only routinely tested gene in the clinical setting for non-syndromic POI is FMR1 (fragile X mental retardation 1) premutation [1]. Overall, this accounts for 2–6% of cases; however, the incidence varies in different racial groups [10,23,24]. FMR1 premutation is associated with POI and expansion of this into a full mutation causes Fragile X mental retardation [25]. FMR1 is located on the X chromosome and the premutation is inherited in an X-linked dominant fashion. This premutation can progress to the full mutation and there are case reports of mental retardation in children born to women with POI [26]; therefore, it is important to screen for this genetic abnormality and to provide the appropriate genetic counseling. However, only 20% of women who carry the permutation will develop POI and the size of the premutation does not seem to have a linear relationship with POI. In fact, women who carry the full mutation actually have the background (1%) risk of developing POI [25,27,28]. Therefore, it has not been possible to predict POI based on the length of the premutation.
Advances in the understanding of hereditary ataxia – implications for future patients
Published in Expert Opinion on Orphan Drugs, 2018
Anna Zeitlberger, Heather Ging, Suran Nethisinghe, Paola Giunti
The most common and only recently recognized adult-onset X-linked ataxia is fragile X-associated tremor/ataxia syndrome (FXTAS). The typical clinical presentation is characterized by intention tremor, gait ataxia, and Parkinsonism in combination with variable cognitive decline [46]. FXTAS is caused by what was previously considered as a premutation of 55–200 CGG·CCG repeats in the 5ʹ untranslated region of the FMR1 gene [46]. Similarly to SCA8, RAN translation results in the transcription of toxic proteins (FXTAS-polyglycine, FXTAS-polyproline, FXTAS-polyalanine) which have been detected in different brain regions [47]. In addition, the RNA-mediated sequestering of proteins has been described [48]. These pathological mechanisms are in contrast to the hypermethylation-associated silencing of the FMR1 gene in fragile X-syndrome [49].
Parenting of children with Down syndrome compared to fragile X syndrome
Published in Developmental Neurorehabilitation, 2018
Audra Sterling, Steven F. Warren
The participants in these analyses are drawn from two separate studies. The FXS sample (n = 19 mother-child dyads) was recruited from a larger longitudinal study of 55 mother-child dyads examining family adaptation to FXS (citations removed for review). We only included boys with FXS in the current analyses to control for gender differences. Eighteen of the mothers had the premutation, and one had the full mutation. The DS sample (n = 19 dyads) was recruited from a separate study on responsivity in DS that included 22 mother-child dyads with DS (citation removed for review). Participants with DS included 8 girls and 11 boys. The children in both groups had a mean age of 39.9 months (range: 22–60 months); they were matched at the group level on chronological age (t(36) = .72, p = .48, d = −.13) and expressive raw scores from the Mullen Scales of Early Learning (MSEL; t(36) = .20, p = .84, d = .10; DS: M = 20.26, SD = 7.40; FXS: M = 19.53, SD = 7.30).19 Given that many of our children were at floor on the subscales, we report raw scores. The groups were matched on maternal education (t(36) = .49, p = .63, d = .15; DS: M = 15.8 years, SD = 1.77; FXS: M = 15.54, SD = 1.61). The groups differed significantly on raw receptive language scores (t(36) = 2.03, p = .050, d = .66; DS: M = 25.58, SD = 8.46; FXS: M = 20.63, SD = 6.46) and approached significance in overall MSEL standard scores (t(30) = 2.01, p = .053, d = .65; DS: M = 57.00, SD = 9.18; FXS: M = 52.00, SD = 5.73).