Co-Occurrence of Fragile X Syndrome with a Second Genetic Condition: Three Independent Cases of Double Diagnosis.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), PPP2R5D--related neurodevelopmental disorder, and 2p25.3 deletion. The co-occurrence of DMD and FXS has been reported only once in a young boy, while in an independent family two affected boys were described, the elder diagnosed with FXS and the younger with DMD. This represents the second case in which both conditions coexist in a 5-year-old boy, inherited from his heterozygous mother. The next double diagnosis had never been reported before: through exome sequencing, a girl with FXS who was of 7 years of age with macrocephaly and severe psychomotor delay was found to carry a de novo variant in the PPP2R5D gene. Finally, a maternally inherited 2p25.3 deletion associated with a decreased level of the MYT1L transcript, only in the patient, was observed in a 33-year-old FXS male with severe seizures compared to his mother and two sex- and age-matched controls. All of these patients represent very rare instances of genetic conditions with clinical features that can be modified by FXS and vice versa.

Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation.

Fragile X syndrome (FXS) is a very frequent cause of inherited intellectual disability (ID) and autism. Most FXS patients have an expansion over 200 repeats of (CGG)n sequence ("full mutation" (FM)) located in the 5'UTR of the FMR1 gene, resulting in local DNA methylation (methylated "full mutation" (MFM)) and epigenetic silencing. The absence of the FMRP protein is responsible for the clinical phenotype of FXS. FM arises from a smaller maternal allele with 56-200 CGG repeats ("premutation" (PM)) during maternal meiosis. Carriers of PM alleles, which are typically unmethylated, can manifest other clinical features (primary ovarian insufficiency (POI) or FXS-associated tremor-ataxia syndrome (FXTAS)), known as fragile X-related disorders. In FXS families, rare males who have inherited an unmethylated "full mutation" (UFM) have been described. These individuals produce enough FMRP to allow normal intellectual functioning. Here we report the rare case of three sisters with a completely methylated PM of around 140 CGGs and detail their neuropsychological function. X inactivation analysis confirmed that the three sisters have a random inactivation of the X chromosome, suggesting that the PM allele is always methylated also when residing on the active X. We propose that in exceptional cases, just as the FM may be unmethylated, also a PM allele may be fully methylated. To our knowledge, females with a methylated PM allele and a mild impairment have reported only once. The study of these atypical individuals demonstrates that the size of the CGG expansion is not as tightly coupled to methylation as previously thought.

Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families.

Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5' UTR of the FMR1 gene. Full mutation alleles (FM) have more than 200 repeats and result in FMR1 gene silencing and FXS. FMs arise from maternal premutations (PM) that have 56-200 CGGs; contractions of a maternal PM or FM are rare. Here, we describe two unaffected boys in two independent FXS families who inherited a non-mosaic allele in the normal and intermediate range, respectively, from their mothers who are carriers of an expanded CGG allele. The first boy inherited a 51 CGG allele (without AGG interruptions) from his mother, who carries a PM allele with 72 CGGs. The other boy inherited from his FM mother an unusual allele with 19 CGGs resulting from a deletion, removing 85 bp upstream of the CGG repeat. Given that transcription of the deleted allele was found to be preserved, we assume that the binding sites for FMR1 transcription factors are excluded from the deletion. Such unusual cases resulting in non-mosaic reduction of maternal CGG expansions may help to clarify the molecular mechanisms underlying the instability of the FMR1 gene.