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FLNA encodes filamin A, an actin-binding scaffold protein, and heterozygous gain-of-function variants cause X-linked dominant skeletal dysplasias including Melnick-Needles syndrome (MNS) (MONDO:0010650). Loss-of-function FLNA mutations underlie periventricular nodular heterotopia, whereas specific missense variants co-occurring with intron retention produce the combined MNS phenotype. Across the literature, over 30 unrelated probands in more than 20 families have been reported with FLNA variants segregating in an X-linked dominant pattern, with multiple pedigrees exhibiting male lethality and female skeletal lesions (PMID:25755106).
Genetic evidence for FLNA in MNS meets ClinGen criteria for a Definitive association. Thirty-three FLNA variants (predominantly missense within exons 3, 22, 26, and 31) have been described in MNS probands, with recurrent alleles such as p.Ala1188Thr and p.Lys1193Pro reported in unrelated families (PMID:29575627, PMID:32814550). Segregation studies include at least 19 additional affected female relatives, with skewed X-inactivation correlating with phenotypic severity in mother–daughter pairs (PMID:27478655). Male hemizygotes typically present with perinatal lethality or severe fetal malformations, underscoring the dominant mechanism and confirming pathogenicity in multiple lineages.
The variant spectrum in MNS comprises exclusively missense changes that alter conserved residues or splice‐site strength, plus rare deep‐intronic NMD‐triggering variants. A prototypic FLNA mutation is c.622G>C (p.Gly208Arg), which produces two aberrant transcripts: one retaining intron 3 and one with a deleterious missense change, both leading to reduced protein levels in lymphocytes under NMD control (PMID:25755106). Other examples include c.3578C>C (p.Lys1193Pro) in exon 22 and c.4420G>A (p.Asp1474Asn) in exon 26, the latter identified in recurrent miscarriages and validated in CRISPR/Cas9 mouse models showing attenuated abdominal muscle migration (PMID:36734119).
Functional studies robustly support a gain-of-function mechanism for skeletal dysplasia and a concurrent loss-of-function impact on neuronal migration. Patient lymphocyte Western blots demonstrate reduced FLNA, while ultradeep sequencing and cycloheximide assays confirm NMD sensitivity of intron-retaining transcripts (PMID:25755106). Mouse knock-in of p.Asp1474Asn recapitulates midline defects and impaired cell migration, and in vitro overexpression or knockdown assays delineate disrupted interactions with actin and binding partners (PMID:36734119).
No studies have refuted the FLNA–MNS association. All reported functional assays, segregation data, and phenotypic concordance across sexes and developmental stages consistently align with a dominant‐negative or neomorphic effect confined to key filamin repeats. While additional structural studies of late filamin domains exceed ClinGen experimental caps, the extant data suffice for a definitive classification.
Clinically, FLNA testing is essential for accurate diagnosis and genetic counseling in families with MNS features, particularly for predicting male lethality versus female survival. Key take-home: FLNA missense variants causing combined gain and loss of function are definitively linked to Melnick-Needles syndrome and warrant inclusion in diagnostic panels for skeletal dysplasia and periventricular heterotopia.
Gene–Disease AssociationDefinitiveOver 30 unrelated probands across >20 families, X-linked dominant inheritance, multiple segregation analyses and functional concordance Genetic EvidenceStrong33 FLNA missense and splicing variants in MNS probands, recurrent alleles with segregation in X-linked dominant pedigrees Functional EvidenceStrongConcordant in vitro and in vivo models demonstrating dual gain- and loss-of-function effects matching human phenotypes |