Heterozygous de novo variants in MACF1 gene were first identified in 2018 (PMID: 30471716) in 9 individuals with lissencephaly, complex brain malformations, global developmental delay, severe intellectual development disorder, axial hyptonia, seizures, dysphagia, strabismus, stereotypies and involuntary movements. In this publication 8 variants were missense and affecting the GAR domain (3 of which recurrent) and one was an in-frame deletion. In 2021 (PMID: 33511591) another proband with a recurrent de novo missense variant was also described and had the same phenotype.
One single report for autosomal recessive inheritance (PMID: 32010038) in two affected brothers with brain malformations, epilepsy and severe developmental delay was not included for the purposes of this curation. Other data about patients harboring variants of this gene and clinical characteristics of schizophrenia (PMID: 26666178), bipolar disorder (PMID: 34100076, 30772743) and sagittal craniosynostosis (PMID: 28808027) were also excluded. In addition, an intragenic duplication (involving exons 1-35 of MACF1) was not scored because it was found in a family with variable neuromuscular symptoms, without mention of any brain malformations, and inherited from a mildly symptomatic mother to three of her four children; two of which had severe symptoms (PMID: 24899269).
MACF1 belongs to spectraplakins and acts as cytoskeletal crosslinker by coordinating with microfilaments, microtubules and intermediate filaments. It is involved in multiple neural processes including neurite outgrowth and neuronal migration. Structurally contains two calponin-homology domains, a plakin domain, a long spectrin-repeat rod domain, two calcium-binding EF-hand domains, a zinc-binding GAR domain (microtubule binding and stabilization), a positively charged Gly-Ser-Arg region and an EB1-binding domain. This gene produces 6 different isoforms via alternative splicing and differential promoter usage.
The gene-disease relationship is also supported by the fact that MACF1 is required for dendritic arborization and axon outgrowth in the developing brain (PMID: 26526844) and that it acts as a positive regulator in the Wnt pathway (PMID:16815997).
In summary, MACF1 is moderately associated with autosomal dominant Lissencephaly spectrum disorder with complex brainstem malformation. This was approved by the ClinGen Brain Malformation GCEP on July 25, 2023 (SOP Version 9).
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