Fragile X premutation and associated health conditions: A review

Abstract

Fragile X syndrome (FXS) is the most common single gene disorder, which causes autism and intellectual disability. The fragile X mental retardation 1 (FMR1) gene is silenced when cytosine-guanine-guanine (CGG) triplet repeats exceed 200, which is the full mutation that causes FXS. Carriers of FXS have a CGG repeat between 55 and 200, which is defined as a premutation and transcription of the gene is overactive with high levels of the FMR1 mRNA. Most carriers of the premutation have normal levels of fragile X mental retardation protein (FMRP) and a normal intelligence, but in the upper range of the premutation (120-200) the FMRP level may be lower than normal. The clinical problems associated with the premutation are caused by the RNA toxicity associated with increased FMR1 mRNA levels, although for some mildly lowered FMRP can cause problems associated with FXS. The RNA toxicity causes various health problems in the carriers including but not limited to fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. Since some individuals with neuropsychiatric problems do not meet the severity for a diagnosis of a "disorder" then the condition can be labeled as fragile X premutation associated condition (FXPAC). Physicians must be able to recognize these health problems in the carriers and provide appropriate management.FMR1, fragile X premutation associated conditions, fragile X-associated neuropsychiatric disorders, fragile X-associated primary ovarian insufficiency, fragile X-associated tremor/ ataxia syndrome, premutation | INTRODUCTIONFragile X syndrome (FXS) is caused by mutations of the fragile X mental retardation 1 (FMR1) gene at Xq27.3. Almost all of the mutations (> 99%) are due to more than 200+ repeats of cytosine-guanine-guanine (CGG) in the FMR1 gene, which is called "full mutation." The CGG expansion leads to methylation at the promoter region of the FMR1 gene and transcriptional silencing which result in fragile X mental retardation protein (FMRP) deficiency. FMRP, which is abundant in neurons, is a regulatory protein in synaptogenesis. 1 The hallmarks of FXS are developmental delay, intellectual disability, and autism spectrum disorder (ASD). Elongated face, prominent and large ears, macrocephaly, and macroorchidism beginning at the pubertal period are also characteristic of FXS. A systematic review and meta-analysis reported that the prevalence of FXS is approximately 1:7143 in males and 1:11 111 in females. 2 In 1-2% of individuals with ASD, FXS was identified. 3 However, FXS is still underrecognized and the availability of fragile X DNA testing is limited, and thus the prevalence may be underestimated.Whenever FXS is diagnosed, fragile X premutation carriers should be sought in the proband's family. The premutation range is 55-200 CGG repeats in the FMR1 gene. In a systematic review and meta-analysis, premutation was detected at a rate of 1:855 in males and 1:291 in females, rates, which were more prevalent ...

The association between mosaicism type and cognitive and behavioral functioning among males with fragile X syndrome

“…Fragile X syndrome (FXS) is the most prevalent inherited form of intellectual disability and is associated with autism spectrum disorder (Hunter et al, 2014). FXS results from an unstable expansion of a cytosine–guanine–guanine (CGG) nucleotide sequence in the promoter region of the FMR1 gene (Tassanakijpanich et al, 2021). The FMR1 gene product is FMRP, an RNA‐binding protein that regulates protein synthesis at synapses (Bagni & Zukin, 2019) and, therefore, plays a critical role in brain development and synaptic plasticity (Martin & Huntsman, 2012).…”

Can FMR1 CGG repeat lengths predict the outcome in ICSI cycles?

“…The main reason for investigating triple CGG repeats on the FMR1 gene has been the prevention and/or diagnosis of psychiatric and/or neurological conditions that have historically been associated with extremely high triple re--expansion and full mutation (Fragile X syndrome > 200 CGG repetition) intervals [26,27]. The current classification of CGG repetition extends to typical (normal), intermediate (gray zone), premutations, and full mutation, so it is based solely on a screening process for psychiatric and neurological risks.…”

Refining reproductive risk for FMR1 premutation carriers in the general obstetric population

“…This condition is generally caused by expansion of CGG trinucleotide repeats in the 5′ untranslated region (UTR) of the FMR1 gene located at Xq27.3 (Hunter et al, 1998). Alleles with greater than 200 CGG repeats are associated with hypermethylation and inhibition of transcription of the FMR1 gene, resulting in a deficiency or absence of the FMR1 protein (FMRP), which leads to the symptoms seen in FXS (Budimirovic et al, 2020; Hagerman et al, 2017; Tassanakijpanich et al, 2021). There are four categories of CGG repeat alleles: normal (<45), gray zone/intermediate (45–54), premutation (PM, 55–200), and full mutation (>200) (Maddalena et al, 2001).…”

“…Females with FMR1 PM alleles are at risk for CGG expansion into a full mutation in offspring, resulting in a child affected with FXS. Additional features associated with PM allele carriers include fragile X‐associated primary ovarian insufficiency, fragile X‐associated neuropsychiatric disorders, executive dysfunction, autoimmune disorders, and fragile X‐associated tremor/ataxia syndrome (Hipp et al, 2016; Hunter et al, 1998; Tassanakijpanich et al, 2021).…”