European Journal of Human Genetics - Fathers’ and Mothers’ support needs and support experiences after rapid genome sequencing

Apathy is a common symptom across a wide range of neurodegenerative and psychiatric conditions, characterised by a loss of goal-directed action. It is associated with faster rates of cognitive and fun...

Background Pathogenic CASK variants are associated with neurodevelopmental disorders of variable severity including X-linked intellectual disability (XLID) and microcephaly with pontocerebellar hypoplasia (MICPCH). Although the number of diagnosed cases is rising, current understanding of the CASK-related neurodevelopmental spectrum is limited. Here, we systematically review the published characteristics of individuals with CASK-related disorder, and compare these to a more recently-diagnosed group. We provide quantitative information about the ranges of adaptive abilities, motor function, visual function and social-emotional-behavioural characteristics, and explore within-group associations. Methods One hundred and fifty-one individuals with CASK variants were identified in published literature. Thirty-one children and young people with CASK variants were recruited to the UK-based Brain and Behaviour in Neurodevelopmental disorders of Genetic Origin (BINGO) project. BINGO-participating caregivers completed a bespoke medical history questionnaire and battery of standardised neurodevelopmental measures. Results Comparing the recently diagnosed BINGO CASK-related disorder group to previously reported individuals, we found consistent prevalence of tone abnormalities, sensorineural hearing loss and epilepsy, but lower prevalence of severe/profound ID, MICPCH, optic atrophy and nystagmus. Areas of frequent difficulty not highlighted in previous reports include sleep difficulties and cerebral visual impairment (CVI). Neurodevelopmental characteristics were highly variable within the BINGO CASK-related disorder group, and group-wide patterns were similar to those observed in other rare genetic conditions. Within the BINGO CASK-related group, epilepsy is significantly associated with ID severity, after controlling for age. Sub-groups with MICPCH or microcephaly only have equivalent ranges of adaptive function, but MICPCH may be associated with more severe motor difficulties. Conclusion The spectrum of neurodevelopmental characteristics associated with CASK-related disorder appears to be broadening with increased access to genome-wide diagnostic testing. Further studies are needed to elucidate the relationships between CASK variants, structural brain development, epilepsy, and neurodevelopmental characteristics.