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
22238415 Clapham (2012): Report of three families with females affected with X-linked periventricular heterotopia. All families had large deletions including all or a portion of FLNA that would lead to loss of function.
11532987 Sheen (2001): Multiple loss of function mutations described in patients with X-linked periventricular heterotopia.

Haploinsufficiency phenotype comments:

Mutations leading to complete loss of function are associated with X-linked periventricular heterotopia which typically affects females and is lethal in males (see Gene Reviews and references above). Some affected males and mildly affected females have been reported with mutations that presumably retain some function. Missense or small insertion/deletion mutations have also been reported in male and female patients with otopalatodigital spectrum disorders (Gene Review: http://www.ncbi.nlm.nih.gov/books/NBK1393/) which are thought to be caused by gain of function. Additionally, three familial cardiac valvular dystrophy families are described, two with missense mutations and one with an intragenic in-frame deletion (Kyndt, 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

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 reported.

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.