ClinGen Dosage Sensitivity Curation Page

FLNA

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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).

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.

Evidence for Triplosenstive Phenotype

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 .

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.