Abstract Number: PB0333
Meeting: ISTH 2022 Congress
Background: Filamin A (FLNA) variants are responsible for a rare X-linked dominant syndromic macrothrombocytopenia mainly associated with nodular brain heterotopia. Absence of FLNA within platelets may help to establish the pathogenicity of candidate variants.
Aims: To assess the value of platelet FLNA quantification in 10 patients (9 females) carrying 8 novel FLNA variants (3 nonsense and 5 missense) and referred for thrombocytopenia and/or dense granule defect.
Methods: Clinical features, platelet count and size, results of platelet aggregation, dense granules analysis, and glycoprotein levels were collected. Intra-platelet FLNA was quantified by whole blood flow cytometry (FC) and immunofluorescence. Genetic variants were identified using a platelet disorders gene sequencing panel.
Results: The three nonsense variants were: c.133C>T (p.Gln45Ter), c.1056delG (p.Thr353LeufsTer32) and c.1120_1125delinsTCTTG (p.Val374SerfsTer2). All patients (n=5) exhibited macrothrombocytopenia (83-130×109/L, 5-10% macroplatelets) associated with extra-hematological manifestations (nodular brain heterotopia in all, ligamentous hyperlaxity and cardiac malformations). In all patients, a FLNA-negative macroplatelets subpopulation (30-35%) was identified using FC and immunofluorescence (Figure.1A). The five missense variants were: c.1354G>A (p.Gly452Ser), c.3755C>T (p.Ala1252Val), c.6791G>A (p.Arg2264Gln), c.568C>T (p.Arg190Trp), and c.5053A>G (p.Thr1685Ala). All variants were predicted deleterious using multiple prediction tools. Two variants were absent from general population databases and three were very rarely reported (GnomAD exome frequency: 1.69×10-5-5.65×10-6). Thrombocytopenia (36-133×109/L) was reported in 4/5 patients. One patient had an isolated dense granule defect. Macroplatelets were detected at a variable level (0-50%). Two patients had associated organ defects (psychomotor delay, cardiac defect, hyperlaxity, liver cytolysis). Brain magnetic resonance imaging, performed in three patients, was normal. The patient carrying the p.Ala1252Val was finally diagnosed with telomeropathy (TERT variant). FC and immunofluorescence analysis did not reveal any negative FLNA platelet subpopulation (Figure.1B).
Conclusion(s): Our results highlight the value of FLNA platelet quantification to investigate the pathogenicity of nonsense FLNA variants. In contrast, quantification of platelet FLNA may not be informative regarding missense variants.
To cite this abstract in AMA style:Ibrahim-Kosta M, Poggi M, Sbarra V, Falaise C, Hezard N, Mourey G, NEDELEC-GAC F, Fiore M, Saut N, Tomeï E, Alessi M, Saultier P. Quantification of platelet Filamin A by flow cytometry and immunofluorescence does not support the pathogenicity of FLNA missense compared to nonsense variants. [abstract]. https://abstracts.isth.org/abstract/quantification-of-platelet-filamin-a-by-flow-cytometry-and-immunofluorescence-does-not-support-the-pathogenicity-of-flna-missense-compared-to-nonsense-variants/. Accessed September 27, 2023.
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