Background

Fragile-X syndrome (FXS) is the most common cause of inherited intellectual disability and the most common identifiable cause of autism.^{Reference McDuffie, Thurman, Hagerman and Abbeduto1,Reference Talisa, Boyle, Crafa and Kaufmann2} Instigated by an expansion of a trinucleotide (CGG) repeat on the FMR1 gene of the X chromosome, FXS results in reduced production of the FMRP protein. Fragile-X premutation carriers (FX-p) have an expansion of between 55 and 200 CGG repeats on the FMR1 gene. The premutation is relatively common within the general population with approximately 1 in 151 women and 1 in 468 men being affected.^{Reference Seltzer, Baker, Hong, Maenner, Greenberg and Mandel3}

Individuals with the FX-p are generally considered to be cognitively unaffected, although mild difficulties in executive function, working memory and information processing skills have been described.^{Reference Grigsby, Cornish, Hocking, Kraan, Olichney and Rivera4} Recent literature strongly indicates that the FX-p is also a risk marker for autistic traits and negative mental health outcomes.^{Reference Kraan, Hocking, Bradshaw, Fielding, Cohen and Georgiou-Karistianis5–Reference Roberts, Bailey, Mankowski, Ford, Sideris and Weisenfeld11} This risk is evident prior to having a child with FXS.^{Reference Gossett, Sansone, Schneider, Johnston, Hagerman and Tassone12,Reference Schneider, Johnston, Tassone, Sansone, Hagerman and Ferrer13} Although negative mental health outcomes are thought to be the most common challenges faced by individuals with the FX-p,^{Reference Hagerman, Protic, Rajaratnam, Salcedo-Arellano, Aydin and Schneider14} research to date has focused primarily on associated physical conditions. To improve awareness of mental health challenges faced by individuals with the FX-p, Hagerman and colleagues^{Reference Hagerman, Protic, Rajaratnam, Salcedo-Arellano, Aydin and Schneider14} proposed the term fragile X-associated neuropsychiatric disorders. This term was supported and adopted by the European Fragile X Network in 2020.^{Reference Johnson, Herring and Richstein15} Greater understanding of these associated conditions is now critical to ensure appropriate and targeted support for individuals with the FX-p and their families.

Fragile-X-associated neuropsychiatric conditions

Women with the FX-p present with a complex set of risk factors that are likely to interact with one another to mediate heightened vulnerability for mental health problems. The most obvious risk factor is the stress associated with caring for a child or children with intellectual disability, here specifically FXS – as all mothers of a child with FXS will have the FX-p. Elevated levels of stress and affective disorder are well documented within the broader intellectual disability and neurodevelopmental disorder literature.^{Reference Totsika, Hastings, Emerson, Lancaster and Berridge16} Further, studies have reported that mothers of children with FXS show more signs of compromised psychological well-being than mothers of children with Down syndrome^{Reference Abbeduto, Seltzer, Shattuck, Krauss, Orsmond and Murphy17} and a strong association between child behaviour and maternal stress and depression has been found in this population.^{Reference Johnston, Hessl, Blasey, Eliez, Erba and Dyer-Friedman18} The way in which the elevated autistic traits in mothers with the FX-p might also contribute to, and interact with, this risk pathway is not known.

Aims

Our aims in this study were:

1. (a) to delineate the behavioural and neuropsychiatric profile of individuals with the FX-p (studies 1 and 2);

2. (b) to evaluate the role of genetics versus environment on the presentation of autistic characteristics and mental health challenges in women with the FX-p (study 1); and

3. (c) to consider how maternal status interacts with the FX-p to confer risk for autistic traits and symptoms of anxiety and depression (study 2).

Study 1: Autistic traits, anxiety and depression in mothers of children with FXS, Smith-Magenis syndrome and autistic children

Participants in study 1

Participant characteristics are shown in Table 1. In total, there were 51 women in the M-FXp group, 59 in the M-ASD group, 27 in the M-SMS group and 44 in the M-TD group who were included in the present study. The groups were comparable for IQ (H(3) = 3.671, P = 0.271) but did differ in age (H(3) = 12.852, P = 0.005), with the M-FXp group being significantly older than the M-TD (P = 0.013) and M-SMS groups (P = 0.043). There was also a significant group difference in education qualifications (χ²(3) = 12.974, P = 0.005); the M-TD group were more likely to have a higher education qualification than the M-FXp (P < 0.05) and M-SMS groups (P < 0.05). Further, there was a significant group difference in household income (χ²(3) = 10.976, P = 0.012); more participants in the M-TD group earned above £45 000 per year than those in the M-FXp group (P < 0.05).

Table 1

Study 1 participant characteristics: chronological age, IQ, education and household income

M-FXp, mothers of children with fragile-x syndrome, with the fragile-x permutation themselves; M-ASD, mothers of autistic children; M-SMS, mothers of children with Smith-Magenis syndrome; M-TD, mothers of typically developing children.

a. Missing IQ data: n = 4 M-ASD group, n = 1 M-SMS group, n = 5 M-TD group.

b. Household income data not declared: n = 5 M-FXp group, n = 1 M-ASD group, n = 4 M-SMS, n = 3 M-TD group.

Study 2: the influence of maternal status on autistic traits and mental health in women with FX-p

Measures, procedures and ethical approval for study 2 are the same as those outlined in study 1 with the exception that both the QRS-F and the PGS were excluded from study 2 as these measures are specific to parental responsibilities.

Participants in study 2

Participant characteristics are shown in Table 2. In addition to the 51 individuals in the M-FXp group and 44 in the M-TD group, there were 17 participants in the NM-FXp group and 28 in the NM-TD group who were included in study 2. The groups were broadly comparable for age and IQ except that, as expected, mothers were older than non-mothers (F(3,136) = 69.41, P < 0.001). There was a significant group difference in level of education qualifications (χ²(3) = 26.92, P < 0.001); the M-TD group was more likely (P ≤ 0.005) and the NM-FXp group was less likely (P ≤ 0.01) to have a higher education qualification than all other groups. Further, there was a significant group difference in household income (χ²(3) = 23.79, P < 0.001); more M-TD participants earned above £45 000 per year compared with all other groups (P < 0.001).

Table 2

Study 2 participant characteristics: chronological age, IQ, education and household income

M-FXp, mothers of children with fragile-x syndrome, with the fragile-x permutation (FX-p) themselves; M-TD, mothers of typically developing children; NM-FXp, non-mothers with the FX-p; NM-TD, typically developed non-mothers.

a. Missing IQ data: n = 5 M-NT group.

b. Household income not declared/missing: n = 5 M-FXp group, n = 3 M-NT group, n = 4 NM-FXp group and n = 2 NM-TD group.

Main findings and comparison with findings from other studies

Consistent with previous research,^{Reference Clifford, Dissanayake, Bui, Huggins, Taylor and Loesch6,Reference Losh, Klusek, Martin, Sideris, Parlier and Piven9} the findings from study 1 indicated that mothers with the FX-p showed significantly higher levels of autistic traits relative to mothers of typically developing children. Specifically, autistic traits within the area of attention to detail was elevated in this group. Mothers of autistic children also reported more autistic traits than mothers of typically developing children with borderline significance (P = 0.020). This pattern of findings was also reflected at the level of cut-off scores thought to be indicative of ‘significant autistic traits’,^{Reference Baron-Cohen, Wheelwright, Skinner, Martin and Clubley20} with more mothers of children with FXS (45%, n = 23) meeting this cut-off relative to the M-TD group (14%, n = 6) and mothers of children with a non-heritable neurodevelopmental disorder associated with significant challenging behaviour: Smith-Magenis syndrome (11%, n = 3). This pattern of findings indicates that mothers of children with FXS who have the FX-p are at significantly greater risk for autistic traits relative to mothers of typically developing children and present a similar level of risk to that reported in mothers of autistic children in the current and in previous studies.^{Reference Wheelwright, Auyeung, Allison and Baron-Cohen21}

Findings relating to mental health and parental stress were also consistent with previous literature.^{Reference Kraan, Hocking, Bradshaw, Fielding, Cohen and Georgiou-Karistianis5–Reference Roberts, Bailey, Mankowski, Ford, Sideris and Weisenfeld11,Reference Abbeduto, Seltzer, Shattuck, Krauss, Orsmond and Murphy17,Reference Johnston, Hessl, Blasey, Eliez, Erba and Dyer-Friedman18} Anxiety, depression and indicators of parental stress were significantly higher in all three groups of mothers of children with neurodevelopmental disorders relative to mothers of typically developing children. Mothers of children with Smith-Magenis syndrome were at particularly significant risk of experiencing severe depression relative to mothers of children with FXS or autistic children. The fact that in all groups there is evidence of high rates of parental stress and mental health challenges, whereas only the mothers of children with FXS and autistic children show evidence of increased risk for autistic traits, suggests that the presence of these traits is not entirely mediated by the stress of caring for a child with a significant level of need, and is more likely to be a population-specific characteristic. The two × two design of study 2 enabled a more precise evaluation of the relative effect of motherhood versus the FX-p.

Consistent with the findings from study 1, study 2 demonstrated a significant main effect of premutation status that did not interact with motherhood, whereby women with the FX-p, regardless of maternal status, showed significantly increased levels of autistic traits and anxiety relative to women without the FX-p. Consistent with findings from Gossett and colleagues^{Reference Gossett, Sansone, Schneider, Johnston, Hagerman and Tassone12} and Schneider and colleagues^{Reference Schneider, Johnston, Tassone, Sansone, Hagerman and Ferrer13} who also report increased risk of autistic traits, depression and obsessive–compulsive symptoms in women with the FX-p who did not have children; these results indicate that the presence of the FX-p confers significant risk for autistic traits and mental health challenges across this population. This risk is not systematically increased by having caring responsibilities for a child or children with a neurodevelopmental disability.

Interpretation of our findings

The findings demonstrate the presence of a subtle and specific behavioural phenotype associated with the FX-p that cannot be fully accounted for by factors associated with parental stress and adjustment. Rather, the findings suggest an increased risk for certain psychological and behavioural characteristics that, for some individuals, present a significant day-to-day challenge. These characteristics, particularly anxiety, may be exacerbated by the stress of caring for a child or children with significant need but are not solely accounted for by such factors. The findings have implications for decision-making pathways regarding testing and diagnosis of siblings and relatives of individuals with the full FXS, who are at risk for the FX-p. Early recognition and identification of these challenges may be important for providing preventative and early intervention and support for women with the FX-p and their families.

Given the heightened prevalence of autism in individuals with the full FXS, the finding of increased risk for broader autism phenotype traits in mothers with the FX-p, as well as in women with the FX-p without children, indicates a pattern of autism heritability that appears to mirror that observed in the wider autism population. Although the majority of cases of autism are thought to result from the interaction of multiple common genetic variants rather than a single rare mutation as in FXS,^{Reference Lai, Sobala-Drozdowski, Zhou, Doering, Faure and Foster30} heritability estimates in autism are higher than for any other medical or psychiatric disorder.^{Reference Tick, Bolton, Happé, Rutter and Rijsdijk25} These traits are thought to be passed on by intergenerational transmission, indeed, the degree of parental autistic traits has been found to predict the degree of child autistic symptoms.^{Reference Lyall, Schmidt and Hertz-Picciotto31} This similarity has implications for our understanding of the aetiological pathways that may underpin the pattern of heritability of autistic traits more broadly and requires further investigation.

The profile of predictive factors for mental health problems differed across participant groups. In mothers with the FX-p and mothers of autistic children, the presence of autistic traits was the strongest predictor of their own mental health outcome. In contrast, the strongest predictor of mental health outcome in mothers of children with Smith-Magenis syndrome was positive affect and in mothers of typically developing children, the strongest predictor was coping skills. This emphasises the detrimental effect that elevated autistic traits can have on mental health, possibly the consequence of masking autistic traits in order to fit in.^{Reference Livingston and Happé32}

Limitations

The findings should be considered in the context of several study limitations. First, the studies relied on self-report data regarding the premutation status of participants and the diagnostic status of participant's children. However, all participants were asked to provide detailed information regarding their diagnostic status (when, where and by whom a diagnosis was made and whether a blood test was carried out). These additional questions provided greater certainty of diagnostic status and enabled us to exclude individuals who had not received a diagnosis via the most appropriate route or from an appropriate clinician. The reliance on self-report data is a broader limitation of the study. Although some studies have evaluated these characteristics in greater detail using observational methods,^{Reference Schneider, Johnston, Tassone, Sansone, Hagerman and Ferrer13} further direct studies are required in order to describe more accurately the behavioural phenotype associated with the FX-p in women.

The small sample size of the NM-FXp (n = 17) group is also a limitation of the study. However, this group of individuals is incredibly difficult to identify given that most women are only made aware of their premutation status after having a child with the full syndrome or premutation. Furthermore, the sample size of the NM-FXp group is broadly in line with other studies that have recruited women with the FX-p who do not have children (for example Schneider and colleagues n = 22^{Reference Schneider, Johnston, Tassone, Sansone, Hagerman and Ferrer13}). Although the sample size of the M-FXp group is larger (n = 51) it is still relatively small and this is likely to have limited statistical power (reflected in several borderline significant findings). Further, given that the Fragile X Society, UK advertised the study to 700 individuals in their membership, the limited response rate in the current study suggests that the sample may not be representative of the wider population of mothers with the FX-p. Further studies with larger sample sizes are needed to overcome these challenges.

Implications

In conclusion, our study findings indicate that women with the FX-p show significantly increased risk for autistic traits and anxiety. This risk is specific to the presence of the FX-p and is not explained by maternal status or the stress of caring for a child or children with a neurodevelopmental disorder. These results strongly support the need for recognition of a behavioural and cognitive phenotype for women with the FX-p and support the newly proposed term of fragile-X-associated neuropsychiatric conditions.^{Reference Johnson, Herring and Richstein15,Reference Totsika, Hastings, Emerson, Lancaster and Berridge16} Early recognition and identification of these challenges will be important for providing appropriate levels of support for women with the FX-p and their families.