Submission Details

X-linked

05/01/2019

The FLNA gene is located on the X chromosome at Xq28 and encodes the widely expressed actin-binding protein filamin A. This protein interacts with a large number of binding partners that include membrane proteins like receptors and channels as well as intracellular signaling molecules. Through these interactions, filamin A participates in a diverse array of cellular functions, including a key role in cell migration and adhesion. FLNA was first reported in relation to X-linked periventricular nodular heterotopia in 1998 (9883725: Fox et al. 1998). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least seven predicted null variants and two missense variants have been reported in eight cases from three publications (9883725: Fox et al. 1998; 26471271: Lange et al. 2015; 19289478: de Wit et al. 2008). In three of these cases the variants occurred de novo. More evidence is available in the literature, but the maximum score for genetic (12 pts.) has been reached. This gene-disease relationship is supported by the expression of Flna in the brain during mouse embryogenesis, particularly in cells involved in neuronal migration as well as in neuronal growth cones (17172441: Feng et al. 2006). This expression pattern, together with the gene function of FLNA, is consistent with the phenotype spectrum associated with disease (21169733: Nakamura et al. 2011). Although heterotopic neurons are not observed in hemizygous FLNA null mice or heterozygous null mice, similar cardiac and vascular defects are observed, and males show embryonic lethality as observed in the human disease (17172441: Feng et al. 2006). In summary, FLNA is definitively associated with X-linked periventricular nodular heterotopia. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. Of note, this gene has also been implicated in otopalatodigital (OPD) spectrum disorders. This gene disease association will be assessed separately.

26471271 9883725 19289478 21169733 17172441