Why the study?
Assigning pathogenicity to FLNA variants is difficult due to X-linked inheritance, overlapping phenotypes, and limited understanding of certain protein domains.
This review provides a comprehensive overview of X-linked filaminopathies, offering insights into clinical phenotypes and molecular approaches for resolving FLNA variants of uncertain significance.
Alerts clinicians to FLNA variants in multisystem disease; extends phenotypic spectrum but leaves open targeted management.
The X-linked filaminopathies represent a diverse group of clinical conditions, all caused by variants in the gene FLNA. FLNA encodes the widely expressed actin binding protein, filamin A that has multiple roles during embryonic development including cell migration, mechanical sensing, and cell signaling. In this review, we discuss the 10 distinct X-linked filaminopathy conditions that between them affect almost all organ systems, including the brain, skeleton, heart, and skin, highlighting the critical role of this protein in human development. We review each of the phenotypes and discuss their pathogenesis, where known. Assigning pathogenicity to variants in FLNA can prove difficult, especially for missense variants and small indels, in-part because of the X-linked nature of the phenotypes, the overlap of phenotypic features between conditions, and poor understanding of the function of certain protein domains. We outline here approaches to characterize phenotypes, highlight hotspot regions within FLNA commonly mutated in these conditions, and approaches to resolving some variants of uncertain significance.
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Wade et al. (2020) studied this question.