Dataset Information

Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene.

ABSTRACT: Fragile X syndrome (FXS) has been reported as the leading cause of mental retardation (MR) that predominantly involves males compared to females. An over-expansion of CGG repeats in the 5' untranslated region of the FMR1 gene plays the primary role in this disease. In this study, we encountered a homozygote female patient affected by FMR1 expansion mutation. Surprisingly, she had inherited her full-mutated alleles from two different ancestors. This condition is an extremely rare case of FXS. After accurate genetic counseling, family members were referred to the laboratory for genetic testing. Karyotype with two X chromosomes was the finding after the G-banding study of the proband. Molecular analysis indicated that she was a female with full-mutated or pre-mutated alleles on both of her X chromosomes. It is a rare phenomenon that we detected in this patient. We have concluded that a combination of allele instability during oogenesis and inheritance of two alleles are the leading cause of MR in the presented case.

SUBMITTER: Vafaeie F

PROVIDER: S-EPMC8357243 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene.

Vafaeie Farzane F Alerasool Masoome M Kaseb Mojaver Nasrin N Mojarrad Majid M

Cureus 20210712 7

Fragile X syndrome (FXS) has been reported as the leading cause of mental retardation (MR) that predominantly involves males compared to females. An over-expansion of CGG repeats in the 5' untranslated region of the FMR1 gene plays the primary role in this disease. In this study, we encountered a homozygote female patient affected by FMR1 expansion mutation. Surprisingly, she had inherited her full-mutated alleles from two different ancestors. This condition is an extremely rare case of FXS. Aft ...[more]

PMID: 34395123

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Project description:BackgroundFragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: ≥ 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS.MethodsThe study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43 years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method.ResultsFemales with FXS had significantly higher levels of FMR1 mRNA (p < 0.001) than males. FMR1 mRNA levels were positively associated with age (p < 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM FMR1 mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced FMR1 (p = 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of FMR1 mRNA were associated with decreased intellectual functioning in FXS males (p = 0.029), but not autism features, when combined with the PM/FM mosaic group.ConclusionIncomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS.

Dataset Information

Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene.

Publications

Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene.

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