Early onset or syndromic epilepsy

Gene: FLNA

Green List (high evidence)

I would support this to be a green gene. See gene reviews for FLNA-related periventricular nodular heterotopia https://www.ncbi.nlm.nih.gov/books/NBK1213/
NB: inheritance is X linked, but males usually have prenatal/early lethality, heterozygous females are often affected.

Created: 21 Nov 2019, 5:49 p.m. | Last Modified: 21 Nov 2019, 5:49 p.m.

Panel Version: 1.425

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Green List (high evidence)

I think FLNA is well recognised as a cause of nodular heterotopia and epilepsy.

Created: 7 Oct 2019, 2:17 p.m. | Last Modified: 7 Oct 2019, 2:17 p.m.

Panel Version: 1.352

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

I don't know

Many phenotypes - one is periventricular nodular heterotopia (XLD) of which epilepsy is common.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Heterotopia periventricular, 1 300049

Publications

• 20014127

Red List (low evidence)

Comment on mode of inheritance: At the Webex call 22nd November 2019, it was noted that want to target FEMALES ONLY for the Heterotopia periventricular phenotype.

Created: 25 Nov 2019, 8:38 p.m. | Last Modified: 26 Nov 2019, 4:06 p.m.

Panel Version: 1.474

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy, and following Green ratings by Alisdair McNeill and Alison Callaway: Agreed that there is enough evidence to rate this gene Green. Kept rating of FLNA as Green.

Created: 25 Nov 2019, 8:33 p.m. | Last Modified: 25 Nov 2019, 8:34 p.m.

Panel Version: 1.433

Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.

Created: 7 Oct 2019, 9:46 a.m. | Last Modified: 7 Oct 2019, 9:46 a.m.

Panel Version: 1.351

Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)

Created: 5 Sep 2019, 2:52 p.m. | Last Modified: 5 Sep 2019, 2:52 p.m.

Panel Version: 1.262

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.

Created: 15 Aug 2019, 10:07 a.m. | Last Modified: 15 Aug 2019, 10:07 a.m.

Panel Version: 1.230

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

PMID:25755106. In a woman and her 3 daughters with a complex phenotype comprising both periventricular nodular heterotopia and Melnick-Needles syndrome, Parrini et al. (2015) identified a c.622G-C transversion in exon 3 of the FLNA gene (G208R). The 3 daughters had onset of seizures in the first decade.

Created: 22 Jul 2019, 12:36 p.m. | Last Modified: 22 Jul 2019, 12:36 p.m.

Panel Version: 1.174

PMID:20014127. In an 18-month-old girl with periventricular nodular heterotopia and seizures, Jefferies et al. (2010) identified a heterozygous 7896G-A transition in the FLNA gene (W2632X).

Created: 22 Jul 2019, 12:36 p.m. | Last Modified: 22 Jul 2019, 12:36 p.m.

Panel Version: 1.174

PMID:15668422. Sheen et al., 2005 report three females with FLNA variants and periventricular heterotopia. One of the females (F8) had seizures and a 116C>G (p.A39G) variant in FLNA.

Created: 22 Jul 2019, 12:36 p.m. | Last Modified: 22 Jul 2019, 12:36 p.m.

Panel Version: 1.174

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 16 variants reported Heterotopia, periventricular 300049. One case of Intestinal pseudoobstruction, neuronal 300048 had seizures at different stages of life from infancy (PMID 17357080), report of de novo epileptic encephalopathy (PMID 23934111).

Created: 3 Sep 2018, 2:27 p.m.

Green List (high evidence)

XLD; but note affected males have also been described, sometimes with ID/features of frontonasal dysplasia.
Seizures are part of the phenotype.

Created: 13 Aug 2018, 11:30 p.m.

Mode of inheritance
Other

Phenotypes
Heterotopia, periventricular, MIM#300049

Variants in this GENE are reported as part of current diagnostic practice