MAP1B – Periventricular Nodular Heterotopia

Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by ectopic neuronal nodules along the lateral ventricles. Classical X-linked PNH arises from FLNA defects, but recent studies implicate additional genes in autosomal dominant forms of the disease. Exome sequencing of 202 sporadic PVNH cases uncovered an excess of deleterious variants in intolerant genes, prompting gene-level collapsing analyses that identified MAP1B as a novel risk locus (PMID:29738522).

Four unrelated probands harbored ultra-rare heterozygous loss-of-function variants in MAP1B, including one de novo variant and one instance of familial segregation from an affected parent. A representative variant is c.2253dup (p.Pro752fs). These variants were genome-wide significant and enriched relative to controls, implicating MAP1B in autosomal dominant PVNH with incomplete penetrance (PMID:29738522).

Clinically, affected individuals presented frontal PVNH often accompanied by perisylvian polymicrogyria (HP:0012650) and epilepsy (HP:0001250). The spectrum consisted exclusively of loss-of-function variants (n = 4), supporting a haploinsufficiency mechanism. One affected relative segregated with the variant, confirming familial transmission and phenotypic concordance.

Functional assessment of Map1b-deficient mice reveals perinatal lethality and profound neural migration abnormalities, indicating a critical role for MAP1B in corticogenesis. Homozygous mutant mice exhibit severe structural brain defects including disrupted axogenesis and neuronal layering, mirroring key features of human PNH (PMID:11085878).

No conflicting reports have been identified. Together, genetic and experimental data support a moderate association between heterozygous MAP1B loss-of-function and Periventricular Nodular Heterotopia. Further case series will strengthen penetrance estimates and variant interpretation.

Key Take-home: Heterozygous loss-of-function variants in MAP1B cause an autosomal dominant form of periventricular nodular heterotopia, warranting its inclusion in diagnostic genetic panels for cortical malformations.

References

• PLoS genetics • 2018 • De novo and inherited private variants in MAP1B in periventricular nodular heterotopia. PMID:29738522
• Molecular and cellular neurosciences • 2000 • Perinatal lethality of microtubule-associated protein 1B-deficient mice expressing alternative isoforms of the protein at low levels. PMID:11085878

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