A potentially deleterious novel FLNA variant could aid early detection of X-linked Inherited diseases in Foetus

Article by Dr. Prachi Gadgil-Fadnis

Filamin A, commonly known as FLNA, is a protein-coding gene that encodes an actin-binding protein. This encoded protein crosslinks the actin filaments, thereby linking them to membrane glycoproteins. A significant function of the FLNA gene is to remodel the cytoskeleton and facilitate cellular motility and signalling. This includes regulation of the skeletal and brain development, formation of the heart tissue and blood vessels, mechanism of blood clotting, skin elasticity, maintenance of the lung tissue and the functioning of the digestive system. FLNA contains an N-terminal actin-binding domain (ABD) and comprises two calponin homology domains, CH1 and CH2, two ROD domains, including 24 Ig repeats. Any defect in the FLNA gene is home to a wide spectrum of conditions. Otopalatodigital spectrum disorder (OPDSD) is an example.

Pathogenic variants in the FLNA gene cause the X-linked hereditary disease known as OPDSD. Due to OPDSD's various symptoms, a final diagnosis may sometimes be delayed. The location of the mutation helps in clarifying the diagnosis due to the presence of overlapping characteristics. OPD2, one of the more severe conditions among OPDSDs, is caused by pathogenic variants that are predominantly localised in CH2 and result in gain-of-function mutations that boost the actin-binding affinity.

A? recent study by Oshina et al. at the National Research Institute for Child Health and Development in Tokyo, Japan, discusses a novel FLNA mutation in a 20-week foetus with severe skeletal dysplasia. The 38-year-old multigravida female carrying the affected foetus had a history of two abortions, and two miscarriages in the first trimester of pregnancy.? During her current pregnancy, an antenatal ultrasound examination at 16 weeks revealed a host of deformities and conditions that led to a strong suspicion of lethal dysplasia.

The authors sequenced the genomic DNA of 4 subjects using Whole-exome sequencing which detected a novel hemizygous variant [c.583G > A (p.G195S)] in the region encoding the CH2 subdomain of the ABD of FLNA. Sanger sequencing of wild-type individuals (father and son), a heterozygous female (mother), and a hemizygous male (20 weeks foetus) was performed to confirm the variant. It was speculated that this potentially deleterious variant was inherited by the foetus from the mother, who was a heterozygous carrier of the variant.

This variant has neither been reported in people with FLNA-related disorders nor been registered in variant databases in general populations. However, it is anticipated to be damaged by the protein function prediction softwares (SIFT, PolyPhen-2 and CADD). The pathogenic domain that harbours the variant is found to be highly conserved. Since glycine is substituted with serine, a significant physicochemical difference may also be observed. The FLNA variation has been labelled as a variant of uncertain significance (VOUS) in accordance with guidelines.

A large number of cases should be used to elucidate the pathogenesis of OPDSD because there haven't been many functional investigations on fatal FLNA mutations. The reported patient's severe phenotype may be caused by the novel FLNA mutation. Since FLNA is essential for the development of the human embryo, it is hypothesised that the previous miscarriages were brought on by the FLNA variation, which is typically fatal in males. However, an early diagnosis could be able to offer potential parents the right genetic counselling services for prospective pregnancies.

References

[1] Oshina, K., Kamei, Y., Hori, A. et al. A novel FLNA variant in a fetus with skeletal dysplasia. Hum Genome Var 9, 45 (2022).

[2] Falet, H. New insights into the versatile roles of platelet FlnA. Platelets 24, 1–5 (2013).

[3] Rosa, J. P., Raslova, H. & Bryckaert, M. Filamin A: key actor in platelet biology. Blood 134, 1279–1288 (2019).

[4] Clark, A. R., Sawyer, G. M., Robertson, S. P. & Sutherland-Smith, A. J. Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders.?Hum. Mol. Genet.?18, 4791–4800 (2009).

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