Genotype profile and genotype-phenotype relationship of patients with CGG repeat number 40 and above in FMR1 gene: Ondokuz Mayis University experience

Aim: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID). It exhibits X-linked inheritance pattern and is more frequently observed in males than females. In addition to ID in full mutant (FM) patients, increased risk of disorders such as premutation carrier-related premature ovarian insufficiency (POI) and Fragile X-associated tremor/ataxia syndrome (FXTAS) is seen. This study aimed to explain the genotype profile of patients with a CGG repeat number of 40 or more in the FMR1 gene and the phenotype-genotype relationship using TP PCR test. Materials And Methods: A total of 130 patients were included in the study. Genomic DNA isolation was performed from samples obtained from the patients. CGG and AGG repeat numbers were determined using TP PCR test. Patients were divided into 4 groups based on CGG repeat numbers according to the American College of Medical Genetics guidelines: FM, premutation (PM), grey zone, and normal alleles. Results: There were 74 female and 56 male patients. Out of them, 34 patients were FM, 43 patients were PM, 15 patients were in the grey zone, and 38 patients had normal allele range. Size mosaicism was detected in 44 patients, with 16 being FM and 28 being PM. Most commonly, there were 2 AGG interruptions and at least 4 AGG interruptions in the patients. Expansion was generally observed in CGG transmissions from mothers to sons, while contraction was generally observed in CGG transmissions from fathers to daughters. ID was present in 100% of FM male patients. Attention deficit hyperactivity disorder was present in 34 patients, and autism spectrum disorder was present in 32 patients. The majority of these patients were FM. There were 23 patients with POI. The rate of POI in PM patients was significantly higher compared to the other three groups. A history of early menopause was present in 48 patients, with 85% of them being FM and PM patients. Two patients had findings compatible with FXTAS. Conclusion: FXS poses a risk for ID in FM patients, POI and additional comorbidities in PM patients. CGG repeats have mitotic and meiotic instability. Therefore, patients should be followed in terms of transmission and additional diseases from the CGG repeat number of 40 and above, where mitotic instability begins. Keywords: Fragile X syndrome, ID, POI, mitotic instability