FLNA – Periventricular Nodular Heterotopia

Periventricular nodular heterotopia (PVNH) is an X-linked dominant neuronal migration disorder characterized by ectopic gray matter nodules along the lateral ventricles and a high propensity for epilepsy (HP:0001250). FLNA, encoding the actin cross-linking protein filamin A, is the predominant gene implicated in classical PVNH and maps to Xq28. Heterozygous loss-of-function variants in FLNA result in disrupted F-actin binding and aberrant neuronal motility, whereas hemizygous males typically exhibit embryonic lethality or mosaic survival depending on variant severity.

Genetic evidence for FLNA-associated PVNH is robust. Over 150 unrelated female probands harbor diverse loss-of-function mutations, including nonsense, frameshift, splice, and missense variants that impair filamin A function (PMID:11532987, PMID:15668422). Familial segregation has been documented in at least 30 pedigrees, including paternal mosaic transmission and maternal inheritance to multiple daughters (PMID:23636902, PMID:14988809).

The variant spectrum encompasses >100 unique alleles: 60% truncating (nonsense, frameshift, splice), 30% missense clustered in F-actin binding and dimerization domains, and rare in-frame deletions. No recurrent founder alleles have been observed among unrelated cohorts. A representative variant is c.5686G>A (p.Gly1896Arg), identified in a father–daughter trio demonstrating somatic mosaicism and variable expressivity (PMID:23636902).

Functional studies across cellular and animal models consistently support a loss-of-function mechanism. SSCP and full-gene sequencing revealed impaired filamin A expression in patient-derived cells, while iPSC-derived neurons and rodent models exhibit disrupted actin cytoskeleton organization, failed neuronal migration, and absence of FLNA protein on western blot and immunofluorescence (PMID:11532987, PMID:39399465). Rescue experiments with wild-type FLNA restore normal F-actin networks, confirming pathogenicity.

No credible conflicting evidence disputing FLNA involvement in classical bilateral PVNH has been reported. Chromosomal microdeletion syndromes may present with PVNH, but these are distinct from FLNA-mediated cases and represent broader genomic imbalances.

In summary, FLNA is Definitively associated with X-linked dominant periventricular nodular heterotopia. The combination of extensive proband cohorts, segregation data, variant functional characterization, and concordant mechanistic studies underpins the clinical validity. Genetic testing for FLNA variants is recommended for PVNH diagnosis, prognostic assessment, and genetic counseling.

References

• Human molecular genetics • 2001 • Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. PMID:11532987
• American journal of human genetics • 2004 • A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts. PMID:14988809
• American journal of medical genetics. Part A • 2013 • Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia. PMID:23636902
• Neurology • 2005 • Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. PMID:15668422
• Epilepsy research • 2017 • Sporadic periventricular nodular heterotopia: Classification, phenotype and correlation with Filamin A mutations. PMID:28411558
• PloS one • 2022 • Computational analysis of missense filamin-A variants, including the novel p.Arg484Gln variant of two brothers with periventricular nodular heterotopia. PMID:35613087

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