Early onset or syndromic epilepsy

Gene: FGFR3

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, 11:59 a.m. | Last Modified: 11 Oct 2023, 11:59 a.m.

Panel Version: 4.110

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene for hypochondroplasia. The variant NM_000142.5(FGFR3):c.1620C>A (p.Asn540Lys) has been reported in at least six unrelated cases of hypochondroplasia (OMIM:146000), in which the patients also display epileptic seizures (PMIDs:12794698; 16222682;17621485 ;2463028; 23165795; 27485793). Biallelic FGFR3 variants have been also been reported in a novel phenotype of achondroplasia, which also includes seizures (PMID: 30160829). Migrating neonatal seizures were also reported in a case of Muenke syndrome (OMIM:602849), carrying the variant: NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)(PMID: 28551036).

Created: 16 Feb 2023, 4:36 p.m. | Last Modified: 16 Feb 2023, 4:36 p.m.

Panel Version: 3.55

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 16 Feb 2023, 4:12 p.m. | Last Modified: 16 Feb 2023, 4:12 p.m.

Panel Version: 3.55

Comment on phenotypes: Isolated seizures have also been reported in cases with: Muenke syndrome, OMIM:602849;Muenke syndrome, MONDO:0011274;SADDAN, OMIM:616482;severe achondroplasia-developmental delay-acanthosis nigricans syndrome, MONDO:0014658

Created: 16 Feb 2023, 3:41 p.m. | Last Modified: 16 Feb 2023, 3:41 p.m.

Panel Version: 3.53

I don't know

Paper by Okazaki et al 2017. States HCH patients with the N540K variant are reported to have medial temporal lobe dysgenesis and epilepsy. Not mentioned on OMIM. Other papers 2017/2018 suggesting link with HCH and epilepsy. Not enough evidence to add to panel and due to the presence of short stature, they will hopefully have been diagnosed on the HCH/ACH panel.

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

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Achondroplasia, 100800; Bladder cancer, somatic, 109800; CATSHL syndrome, 610474; Cervical cancer, somatic, 603956; Colorectal cancer, somatic, 114500; Crouzon syndrome with acanthosis nigricans, 612247; Hypochondroplasia, 146000; LADD syndrome, 149730; Muenke syndrome, 602849; Nevus, epidermal, somatic, 162900; SADDAN, 616482; Spermatocytic seminoma, somatic, 273300; Thanatophoric dysplasia, type I, 187600; Thanatophoric dysplasia, type II, 187601;

Publications

• 27485793

I don't know

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 this gene should be rated Amber because the Craniosynostosis panel is more appropriate for testing. Demoted from Green to Amber.

Created: 15 Aug 2019, 10:06 a.m. | Last Modified: 15 Aug 2019, 10:06 a.m.

Panel Version: 1.228

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:28551036: Okubo et al., 2017 report a 3 year old Japanese boy with Muenke syndrome who had repetitive apneic spell followed by focal status epilepticus in the early infancy. Thee long-term seizure prognosis was favorable. WES revealed a heterozygous variant in FGFR3: c.749C>G, p250A.

Created: 22 Jul 2019, 12:25 p.m. | Last Modified: 22 Jul 2019, 12:25 p.m.

Panel Version: 1.173

Green List (high evidence)

Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.

Created: 14 Nov 2018, 12:02 p.m.

Comment on phenotypes: added additional relevant phenotype Muenke syndrome Millichap, J.G., 2012. Epilepsy in Muenke Syndrome. Pediatric Neurology Briefs, 26(12), pp.93–93. DOI: http://doi.org/10.15844/pedneurbriefs-26-12-6 : A review of 789 published cases of Muenke syndrome with neurological complications identified epilepsy in 6 cases, with intracranial anomalies in 5. The intracranial anomalies were agenesis of the corpus callosum, hemimegalencephaly, and porencephaly. In the review of 58 patients with Muenke syndrome in the Washington, DC cohort, 7 (12%) had epilepsy and 4 survived neonatal apnea. Patients with Muenke syndrome should be monitored for apnea and seizures.

Created: 14 Nov 2018, noon

Comment on publications: Hypochondroplasia and FGFR3 variants are associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy and was first reported PMID: 24630288 (2014). Subsequent cases PMID: 27485793, PMID:23649205, PMID:12794698. In addition, patients with with Muenke syndrome (MS) also show similarities in early-onset temporal lobe-related seizures PMID:23044018, PMID:12794698, PMID:18000976.

Created: 14 Nov 2018, 11:54 a.m.

Comment on phenotypes: Added phenotype suggested from expert review that indicate relevance to inclusion on the Genetic Epilepsy Syndromes panel.

Created: 14 Nov 2018, 11:25 a.m.

Green List (high evidence)

This condition is well documented as being associated with epilepsy. It can be difficult to recognise clinically, particularly in infancy and therefore we consider this gene merits as much inclusion in an Epilepsy panel as other syndromic diagnoses (e.g. EFTUD2 etc).

Created: 22 Jan 2020, 9:23 a.m. | Last Modified: 22 Jan 2020, 9:23 a.m.

Panel Version: 2.0

There are reports of seizures in hypochondroplasia (likely related to temporal lobe abnormalities).

Created: 13 Aug 2018, 12:40 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypochondroplasia, MIM#146000

Publications

• 24630288
• 27485793
• 23649205
• 12794698

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