A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders

Abstract

Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.

Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males

“…Robinson et al (2013) analyzed two separate, large studies of twins and found that the females in those studies were more protected from autistic impairments relative to the males, indicating that females may require larger etiologic loads than males to manifest the autistic phenotype. Jacquemont et al (2014) found that females with an ASD diagnosis have a higher mutational burden, meaning that it takes more mutations to trigger an ASD diagnosis in females than it does for males, indicating that females have greater resistance to the etiologies of an ASD diagnosis than males. Moreover, the rise in the incidence and prevalence of neurodevelopmental disorders has paralleled the increase in the widespread exposure to and the bioaccumulation of chemical neurotoxicants (Genuis and Kelln 2015).…”

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

“…To examine that possibility, these analyses test etiologic structure in a group of ASD individuals identified for extreme behavioral and language impairments. Last, cognition and case severity are associated with the ASD sex ratio, which may also be indicative of patterns in etiologic structure (30). The male to female ratio in ASD, which is estimated to be 4:1 overall, increases across the IQ range (31).…”

Microarreglos cromosómicos en 236 pacientes chilenos con trastornos del neurodesarrollo y anomalías congénitas

“…12 , ambos estudios muestran una mayor derivación de pacientes del sexo masculino por sobre el femenino. Esto se explicaría por la mayor prevalencia de TN en hombres que en mujeres, reflejando la contribución de enfermedades ligadas al cromosoma X recesivas en dicha diferencia 19 y un "factor protector femenino" frente a este tipo de trastornos 20 . En relación a la edad de los probandos estudiados, la mediana de la edad se encuentra alrededor de los 5 años en ambos estudios.…”

“…Al realizar el análisis asociativo entre un resultado alterado por CMA y diversas características de los pacientes con cariotipo normal, detectamos una clara asociación entre el sexo del paciente y la posibilidad de encontrar una VLP/VP. Esta situación confirma para la población chilena lo descrito en estudios internacionales 20,21 . Se sabe que las mujeres presentarían un "factor protector" para el desarrollo de TN.…”

“…Tasa diagnóstico de los microarreglos cromosómicos en Chile -V. Faundes et al de estos trastornos, la probabilidad de encontrar una etiología genética es mayor, ya sea por algún desbalance cromosómico 20 o por mutaciones puntuales deletéreas 21 . Aunque la explicación exacta para este fenómeno no se conoce, se ha visto que las variantes genéticas que regularían rasgos antropométricos y polimorfismos en el cromosoma X darían cuenta de esta diferencia 22 .…”