Women who are heterozygous for the full FMR1 mutation are less cognitively impaired than men, with about one-third presenting with ID and the rest exhibiting IQs in the borderline to low normal range [11, 16, 17]. Although the majority of women with FXS are not intellectually disabled, they often manifest a wide range of psychiatric and cognitive impairments, including anxious disorders, attention deficit-hyperactivity disorders, ASD and executive deficits [24, 25]. In women as well as in men with FXS, the literature reports a strong association between ID and autistic features, with individuals with a lower IQ being more likely to be diagnosed with autism [8–10, 12, 14, 15, 20, 26]. A negative correlation between IQ scores and the intensity of autistic symptoms, as measured with the ADOS, was observed in men and women [13, 15]. The level of cognitive impairment is a major predictor of autistic behavior in FXS, stronger than FMRP levels in lymphocytes [13, 27]. These findings would seem to support the suggestion that the occurrence of autistic features in individuals with genetic syndromes and ID is largely the consequence of the cognitive deficit, which decreases their compensatory capacity . Here, we describe the case of two sisters carrying a full mutation of FMR1 with high-functioning ASD, suggesting that autistic features can emerge independently from ID, at least in women. It should be noted, however, that both our patients have an IQ that is low relative to estimates based on familial intelligence, as shown previously in women with FXS . In agreement with our findings, a previous study found a lack of correlation between autistic behaviors and IQ among girls with FXS . Thus, fragile X mutations can manifest in a wide variety of clinical diagnoses crossing categorical boundaries, specifically ID and ASD. The mechanisms involved in the determinism of specific trajectories remain to be elucidated and could be influenced by genetic, epigenetic and environmental processes .
The prevalence of women with high-functioning ASD and FXS is probably underestimated because FXS testing is not systematically included in the etiological screening of patients with high-functioning ASD. In the absence of a family history of ID, premature ovarian failure or Parkinsonism, the search for FMR1 abnormalities is usually not recommended in patients with high-functioning ASD (American Academy of Pediatrics, ). Shyness or social anxiety, commonly mentioned in studies of women with FXS, could be, at least in some cases, misinterpretations of symptoms belonging to the autism spectrum. Also, mild manifestations of ASD are not evaluated or are misevaluated in most reports by the use of inadequate clinical instruments to explore social and communicative deficits in patients with FXS. Thus, if ASD were indeed underestimated in high-functioning patients with FXS, one could suggest that ID and ASD could be phenotypic variants, spanning from ID without ASD to ASD without ID. Specifically in women with FXS, the significant heterogeneity reported for cognitive impairment ranging from severely impaired to normal IQ, or even high IQ in rare cases , could also be true for autistic symptoms, with some individuals presenting independence between both dimensions, as shown for many other genetic disorders implicated in the etiology of ASD . In particular, many X-linked ID genes have been associated with a profound phenotypic heterogeneity and can be disrupted in individuals without ID. For example, NLGN4X mutations are involved in a wide spectrum of phenotypes, ranging from mild isolated ID without communication deficits to Asperger syndrome with normal intelligence (for review see ).
The phenotypic severity of full mutations in women is widely assumed to be determined by X inactivation [18, 19]. However, in our patients, the proportion of active normal alleles was approximately at equilibrium (0.55) in both cases. This contrasts with previous findings, in which women who are phenotypically normal have a skewed X inactivation pattern in favor of the inactive X carrying the mutation [18, 19]. Additional mechanisms may underlie the variable expressivity observed in FXS. First, the individual genetic background may modulate the FXS phenotype. In our proband, however, the search for rare CNVs did not reveal mutations in other genes that could explain the development of autistic features independently of ID. Second, variations in the FMRP level resulting from mosaicism of the FMR1 repeat expansion or incomplete FMR1 promoter methylation [13, 35] can also impact the phenotypic variability observed in patients. For example, there are several reports of male patients with FXS with learning disability but not ID, with partial FMRP expression arising from transcription of unmethylated alleles , including a male with Asperger syndrome . In the sisters reported here, the mutated alleles were fully methylated. Finally, the partial block in 21-dehydrogenase reported in Patient 1 could potentially explain why she was more severely affected than her younger sister. Girls with congenital adrenal hyperplasia have more autistic traits than their unaffected sisters, suggesting that prenatal exposure to high levels of testosterone increases the vulnerability to ASD .