Novel MAP1B loss-of-function variant associated with periventricular nodular heterotopia 9 and literature review on genotype-phenotype associations of MAP1B.

Background: Periventricular nodular heterotopia 9 (PVNH9) arises from defective neuronal migration, which leads to the accumulation of ectopic neurons near the lateral ventricle. PVNH9 is caused by a heterozygous mutation in the microtubule-associated protein 1B (MAP1B) gene.

Methods: We report a PVNH9 family with a MAP1B variant. Trio whole-exome sequencing (WES) was performed to investigate the underlying genetic defects of the family. In vitro functional experiments, including messenger RNA (mRNA) splicing validation, quantitative polymerase chain reaction (qPCR) and western-blotting, were performed to determine the pathogenicity of the novel variant of MAP1B.

Results: WES showed that both the patient and her father carried a heterozygous MAP1B variant (c.7091 dup). Sanger sequencing confirmed that this variant occurred de novo in the father. In vitro functional experiments, mRNA splicing verification indicated normal splicing for both wild-type and mutant types. The qPCR and western blot analyses demonstrated significantly reduced mRNA and protein expression, respectively, in the mutant compared with that in the wild-type. Additionally, by comprehensive summary on genotype-phenotype associations of MAP1B in previously reported literatures, we found that loss-of-function (LOF) variants in MAP1B mainly lead to PVNH-related neurological symptoms, while patients with missense variants may only present with deafness.

Conclusions: We clarified the genetic diagnosis for the family. Additionally, this study reveals a novel LOF variant in MAP1B and provides a comprehensive overview of MAP1B genotype and phenotype, aiding in the diagnosis and genetic counseling.