Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic...

ASXL3-related disorder is a highly heterogeneous neurodevelopmental disorder, with increasing reports of inherited and recurrent variants indicating substantial intrafamilial phenotypic variability, as well as the possibility of interfamilial phenotypic variability.

In this study, we conducted a detailed genotype-phenotype review of 204 individuals from the literature, including the International ASXL3 Natural History Study (IRAS: 316055). Statistical comparisons were made between individuals with variants leading to no protein product (nonsense-mediated messenger RNA decay [NMD], n = 87) and those with protein-truncating variants (no-NMD, n = 117). Phenotypes in 2 mutational clusters, mutational cluster region 1 (MCR1) (c.1095_2237, exon 11; n = 66) and mutational cluster region 2 (MCR2) (c.3043_4906, exon 12; n = 101), were also analyzed. Clinical details of individuals with recurrent variants were compared, along with a visual representation of the genotypes associated with some rarer clinical presentations. We also describe the clinical details of families with inherited ASXL3 variants.

Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a statistically increased prevalence in the NMD and MCR1 groups. Intellectual disability and global developmental delay were more severe in the NMD and MCR1 groups and were significant for the MCR1/MCR2 comparison (P = .0031 and P = .0183). Although autistic features were observed across all groups, the no-NMD and MCR2 cohorts had a higher proportion of individuals with formal autism diagnoses.

We describe extensive phenotypic variability through the largest-to-date series of families with inherited pathogenic or likely pathogenic ASXL3 variants (as per the American College of Medical Genetics and Genomics classification) and a review of the clinical details of unrelated individuals with recurrent variants. The family reports emphasize the possibility of additional, yet currently unidentified, factors influencing phenotypic expression or, alternatively, may reflect uncertainty about the pathogenicity of inherited ASXL3 variants. Our data set facilitates comprehensive molecular comparisons to elucidate genotype-phenotype correlations, overcoming the limitations of previous studies with small sample sizes or an absence of statistical analysis. These findings contribute to a deeper understanding of the underlying pathophysiological mechanisms.