ClinGen Dosage Sensitivity Curation Page

FLNA

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16684786 Parrini et al., (2013) identified 25 loss of function sequence variants (frameshift, splice site, nonsense) in 40 patients with periventricular nodular heterotopia (PNH). FLNA variants were found in 100% of familial cases with X-linked PNH (10 families) and in 26% of sporadic cases with classical bilateral PNH (affected females: 93% and affected males 7%).
23032111 Reinstein et al., (2013) reported FLNA variants in 11 males and females with a wide spectrum of connective tissue and vascular anomalies. The variants included frameshift, splice site, nonsense, and a deletion of exons 2-13 detected by MLPA. The authors identified 4 de novo loss of function variants, including the exonic deletion. The authors suggested that the variants leading to disease in males were likely to be hypomorphic to permit survival in hemizygotes. The diagnosis of X-linked periventricular heterotopia (PH) was established by neuroimaging in individuals with variable clinical manifestations including seizures, developmental delay, muscle weakness, and family history of PH.
26471271 Lange et al., (2015) described 39 FLNA variants, mainly truncating, in 47 patients with periventricular nodular heterotopia (PVNH). Missense variants were only identified in 2 patients. The authors reported 10 de novo variants (1 missense, 2 nonsense, 4 frameshift, 1 splice site, 1 exonic deletion: exons 40 to 3?UTR, and 1 complex genomic rearrangement: deletion of exon 46 and duplications exons 4-22).

Haploinsufficiency phenotype comments:

Mainly loss of function variants of FLNA are associated with X-linked dominant periventricular nodular heterotopia (PVNH). Seizures, vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, The substantial majority of individuals with FLNA-related PVNH are females since hemizygosity for null variants characteristically leads to male embryonic lethality. Variants leading to disease in males are likely to be hypomorphic to permit survival in hemizygotes. Jenkins et al., (2018) reported familial and de novo loss of function variants of FLNA in individuals with periventricular nodular heterotopia (PVHN), and additional abnormalities including congenital intestinal pseudo-obstruction (CIPO), joint laxity, translucent skin (PMID 5:29024177). Ieda et al., (2018) reported a de novo nonsense heterozygous variant in FLNA in a female patient with periventricular nodular heterotopia, Ehlers-Danlos-like collagenopathy, and macrothrombocytopenia (PMID 29449050). Heinzen et al., (2018) described 9 de novo variants in FLNA (1 missense, 1 inframe, 1 frameshift, 6 nonsense) in patients with periventricular nodular heterotopia (PVHN) (PMID 29738522). Further, hemizygous sequence variants of FLNA can cause several X-linked recessive OMIM phenotypes in males: X-linked cardiac valvular dysplasia (#314400), congenital short bowel syndrome (#30048), FG syndrome 2 (#300321), frontometaphyseal dysplasia (FMD; #305620), neuronal intestinal pseudoobstruction, (#300048), Melnick-Needles syndrome (MNS; #309350), otopalatodigital syndrome type I (OPD1; #311300), otopalatodigital syndrome type II (OPD2; #304120), and terminal osseous dysplasia (#300244). Females with a pathogenic FLNA alteration may have variable or mild manifestations of some of these disorders. However, periventricular nodular heterotopia is not usually a finding in these phenotypes, and the FLNA pathogenic variants associated with them are felt to be gain of function (Gene Review: https://www.ncbi.nlm.nih.gov/books/NBK1213/). Additionally, three familial cardiac valvular dystrophy families are described, two with missense mutations and one with an intragenic in-frame deletion (Kyndt et a., 2007, PMID: 17190868).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
24098143 Sajan et al., (2013) reported a male patient with cerebellar hypoplasia with an 0.49 Mb duplication of Xq28 involving entire FLNA .

Triplosensitivity phenotype comment:

One patient with periventricular heterotopia is reported who has a large duplication (1.9 Mb) which includes FLNA and many other genes, PMID: 9883725 and 9311743. Focal duplications of FLNA alone have not been associated with an established clinical phenotype.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.