A novel de novo missense variant in ASH1L associated with mild autism spectrum disorder and an uneven cognitive profile: a case report.

Researchers found a new genetic change in a 6-year-old boy with mild autism, ADHD, and speech delays. The child had average verbal skills but struggled with visual-spatial tasks. Advanced genetic testing found a change in the ASH1L gene that may explain his condition. This shows that genetic changes in this gene can cause milder autism symptoms, not just severe ones.

This case report describes a 6-year-old male with mild autism spectrum disorder, ADHD, and expressive language disorder who had a novel genetic variant in the ASH1L gene. The child showed an uneven cognitive profile with average verbal abilities but below-average nonverbal reasoning. Whole-genome sequencing identified a de novo missense variant (c.4043A > G) in ASH1L that was absent in population databases and predicted to be damaging. This case expands the known spectrum of ASH1L-related disorders, demonstrating that missense variants can be associated with milder neurodevelopmental outcomes rather than uniformly severe presentations.

The findings highlight the importance of comprehensive genomic analysis when targeted genetic testing is uninformative.

Supports considering comprehensive genomic testing when targeted panels are uninformative. ASH1L variants may cause milder autism presentations than previously recognized. Cognitive profiling may help identify specific patterns associated with ASH1L-related disorders.

Single case report with one patient limits generalizability. Variant classified as uncertain significance. Long-term developmental outcomes unknown. No functional studies to confirm variant pathogenicity.

ASH1L-related intellectual developmental disorder represents an emerging neurodevelopmental syndrome with significant phenotypic heterogeneity (Cordova et al. in Genes (Basel). 15(4):423, 2024). Comprehensive genomic analysis demonstrates superior diagnostic yield compared with targeted approaches in complex neurodevelopmental presentations (Srivastava et al. in Genet Med. 21(11):2413-2421, 2019). This report describes a 6-year-old Central Asian (Uzbek) male patient with a history of global developmental delay who was diagnosed with mild autism spectrum disorder, attention-deficit/hyperactivity disorder, and a developmental expressive language disorder. Neuropsychological assessment revealed an uneven cognitive profile with average verbal abilities but below-average nonverbal reasoning.

After uninformative targeted genetic panels, trio whole-genome sequencing identified a novel de novo heterozygous missense variant in ASH1L c.4043A > G (p.Lys1348Arg). This variant, absent in population databases, was classified as a variant of uncertain significance. However, in silico analysis predicted this variant to be probably damaging, and therefore, it emerged as the strongest candidate to explain the patient's phenotype. This case expands the known phenotypic spectrum of ASH1L-related disorders, demonstrating that a de novo missense variant can be associated with a milder neurodevelopmental phenotype, including borderline-to-average intellectual ability.

These findings challenge suggestions that missense variants uniformly lead to more severe outcomes and underscores the importance of comprehensive genomic and deep clinical characterization to refine our understanding of gene-disease relationships.