An international ASXL3 natural history study: deep phenotypic analyses including detailed reports of a milder phenotype, novel associations, and clinical recommendations

Natural History Studies can help inform clinician and caregiver expectations, form the basis of management guidelines, and provide a comparator for therapeutic intervention. In rare conditions, where collection of prospective longitudinal data is untimely and impractical, quasi-natural history data—from multiple individuals of different ages—provides an alternative approach. A detailed genotype–phenotype analysis of 64 individuals with pathogenic or likely pathogenic ASXL3 variants was carried out, comprising qualitative and quantitative data. The majority of data was collected through direct clinic consultation with the individual and/−or caregiver(s). We report significant phenotypic variability, but improvement trends in feeding, hypotonia, verbalisation, and motor skills over time. Findings include: an increased prevalence of antenatal and neonatal structural anomalies, an emerging renal phenotype, a tendency for poor post-natal growth (with novel reports of obesity later in childhood), and a lower-than-expected prevalence of seizures (compared to the existing literature). We also provide the first qualitative descriptions of several mildly affected probands, at different ages. Our recommendations include: baseline renal imaging after diagnosis, and Dental and Ophthalmological follow-up for all. We describe the largest-to-date cohort of individuals with ASXL3-related disorder, including 24 novel variants, novel clinical findings, quasi-natural history trends, management insights, and recommendations.