Domain specific phenotypic expansion associated with variants inMACF1
Abstract
Purpose
While heterozygousde novomissense variants in the microtubule-binding GAR domain of Microtubule-actin cross-linking factor 1 (MACF1) cause Lissencephaly 9 with Complex Brainstem Malformations [MIM #618325], the phenotypic impact of variants outside this domain remains unclear.
Methods
Through collaborative efforts, we assembled a cohort of 10 affected individuals from 8 unrelated families with either biallelic or monoallelic non-GAR domainMACF1variants who exhibit partially overlapping yet unique phenotypic traits. Combined with previously reported cases, we analyzed genotype and phenotype data from 29 individuals using Human Phenotype Ontology (HPO)-based unsupervised hierarchical clustering.
Results
Clustering revealed two distinct phenotypic signatures, suggesting domain-specific effects. Variants outside the GAR domain associate with broader neurodevelopmental phenotypes and variable craniofacial and skeletal expressivity. Additionally, enrichment analysis (p < 0.001) using OMIM HPO sets supported these findings. In contrast to the GAR domain’s strong correlation with lissencephaly and brainstem malformations, biallelic non-GAR domainMACF1variants were linked to diverse developmental anomalies.
Conclusion
These results expand the phenotypic spectrum ofMACF1-related disorders and highlight the relevance of domain-specific variant effects. Comprehensive genetic and phenotypic assessments are essential for understanding the role ofMACF1in development, informing diagnosis, and guiding future research on cytoskeletal regulation in neurodevelopment.
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