FLNA – otopalatodigital syndrome type 2

Otopalatodigital syndrome type 2 (OPD2) is an X-linked dominant skeletal dysplasia characterized by facial dysmorphism, cleft palate, digital anomalies, and in rare cases central nervous system malformations. Affected individuals frequently present with hearing impairment, omphalocele, fibular aplasia, bowing of long bones, and hallmark craniofacial features such as bifid tongue and corneal clouding. The spectrum of anomalies has recently expanded to include Dandy–Walker malformation, implicating FLNA in neurodevelopmental as well as skeletal processes.

Gain-of-function missense variants in FLNA underlie OPD2, producing an abnormal actin‐binding scaffold that disrupts normal morphogenesis. Two hemizygous mutations—c.514C>G (p.Leu172Val) and c.613T>C (p.Cys205Arg)—were reported in male infants with OPD2 presenting atypical features including bifid tongue and Dandy–Walker malformation (PMID:21412975; PMID:27625837). A multicenter study of 27 probands demonstrated 11 distinct FLNA missense mutations in 15 unrelated families, with segregation in 20 affected relatives, confirming X-linked dominant inheritance and recurrent gain-of-function effects (PMID:27193221).

Genetic evidence includes 17 probands with segregating FLNA missense variants and 20 additional affected relatives across three cohorts. All variants are missense changes clustering in regulatory domains of filamin A, consistent with altered cytoskeletal interactions. The recurrent c.620C>T (p.Pro207Leu) mutation exemplifies this spectrum and has been documented in multiple families with characteristic OPD2 features.

Mechanistically, FLNA gain-of-function variants enhance aberrant binding to actin and partner proteins, leading to dysregulated cell signaling and morphogenesis. Structural studies place these mutations in immunoglobulin-like repeats critical for mechanosensing, supporting a dominant‐negative or neomorphic effect on FLNA’s scaffolding functions.

Based on 17 genotyped probands, 20 segregating relatives, and concordant experimental data, the gene–disease association for FLNA and OPD2 is classified as Strong. Genetic evidence meets the ClinGen genetic cap with multiple unrelated families and clear segregation, while functional data provide Moderate support for a gain-of-function mechanism.

Key Take-home: Gain-of-function FLNA missense mutations cause X-linked dominant otopalatodigital syndrome type 2, guiding molecular diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2011 • Bifid tongue, corneal clouding, and Dandy-Walker malformation in a male infant with otopalatodigital syndrome type 2. PMID:21412975
• Journal of pediatric genetics • 2013 • Otopalatodigital syndrome type 2 in a male infant: A case report with a novel sequence variation. PMID:27625837
• Journal of human genetics • 2016 • Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. PMID:27193221

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