Global developmental delay and focal seizures in individuals with de novo truncating MACF1 variants

Microtubule and actin crosslinking factor 1 (MACF1) plays a critical role in cytoskeletal regulation. Pathogenic variants in MACF1 are associated with a heterogeneous range of phenotypes, including epilepsy, intellectual disability, developmental delay, brain malformations, and hypotonia. This study aims to report two novel MACF1 variants and further explore the genotype-phenotype correlations and pathogenic mechanisms of MACF1-related disorders. We identified two Chinese patients with de novo heterozygous MACF1 variants. Patient 1 carried a frameshift variant (c.18699_18700del, p.V6234Dfs*2) in the spectrin repeats domain (SRD) and presented with global developmental delay. Patient 2 harbored a nonsense variant (c.19657 C > T, p.Q6533*), also located in the SRD. This patient exhibited focal seizures that were readily controlled with valproic acid and perampanel, along with borderline intelligence, oppositional behavior, and hyperactivity. A review of the literature indicated that variants linked to neuropsychiatric disorders tend to cluster within the SRD, likely acting through a loss-of-function (LoF) mechanism and as risk factors for these type of disorders. Furthermore, the two truncating MACF1 variants we reported most likely act through haploinsufficiency. Our findings broaden the phenotypic spectrum of MACF1-associated disorders and provide additional evidence for genotype-phenotype correlations. The results also support the role of haploinsufficiency as a possible pathogenic mechanism in de novo MACF1 variants.