Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses
Abstract
Purpose: 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.
Methods: 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.
Results: 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…
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