Domain specific phenotypic expansion associated with variants in MACF1

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Heterozygous de novo missense variants in the GAR domain of Microtubule-actin cross-linking factor 1 (MACF1) are known to cause Lissencephaly 9.
• The phenotypic consequences of MACF1 variants located outside the GAR domain have not been well-characterized.

Purpose of the Study:

• To investigate the phenotypic impact of MACF1 variants outside the GAR domain.
• To delineate the spectrum of disorders associated with non-GAR domain MACF1 variants.

Main Methods:

• Analysis of genotype and phenotype data from 29 individuals with MACF1 variants (10 from a new cohort and 19 previously reported).
• Utilized Human Phenotype Ontology (HPO)-based unsupervised hierarchical clustering to identify distinct phenotypic signatures.
• Performed enrichment analysis using OMIM HPO sets to support findings.

Main Results:

• Clustering identified two distinct phenotypic groups, indicating domain-specific effects of MACF1 variants.
• Non-GAR domain variants are associated with broader neurodevelopmental phenotypes, including variable craniofacial and skeletal abnormalities.
• In contrast to GAR domain variants linked to lissencephaly, non-GAR domain variants (biallelic) are associated with diverse developmental anomalies.

Conclusions:

• The study expands the known phenotypic spectrum of MACF1-related disorders.
• Domain-specific variant effects in MACF1 are relevant for understanding its role in development.
• Comprehensive genetic and phenotypic assessments are vital for diagnosis and future research on MACF1 and cytoskeletal regulation in neurodevelopment.