Early onset or syndromic epilepsy

Gene: OPHN1

I don't know

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: Green.

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

Panel Version: 1.189

Green List (high evidence)

XLR mental retardation with cerebellar hypoplasia and distinctive facial appearance. Portes et al, 2004 - looking at a family of 4 aff males (1 bp del) and another unrelated female patient with an X:12 balanced translocation - all had early onset complex partial seizures. Phillip et al, 2003 - 2 families where 4 males and 1 male respectively affected - no mention of seizures (2 diff mutations identified). Bergmann et al 2003 - German descent family - 5 aff brothers - features included seizures - OPHN1 deletion. Chabrol et al, 2005 - family with 2 aff males - no mention of seizures. Al-Owain et al, 2011 - Saudi family - 4 boys and 1 girl aff. Proband had partial complex seizures other brothers similarly affected although seizure disorder variable, sister also had seizures - intragenic 68kb del spanning exons 7-15. Zanni et al, 2005 - 4 diff novel variants - 4 unrelated families - no mention of seizures. Moortgat et al, 2018 - 17 individuals from 4 families: family A: 4 aff males and 4 aff females across 3 generations - no epilepsy, Family B: 2 aff males and asympt mum - 1 male had generalised tonic-clonic seizures, Family C: French 4 generation family 6 aff males and 2 asymp females - no affecteds had seizures, Family D: Aff individual - had seizures. Variants detected in all families splice site, nonsense and 2 missense - family D mosaic. Looking at table in paper epilepsy ~50% of cases (lists previously reported cases).

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
Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, 300486

Publications

• 18512229
• 12805098

Comment when marking as ready: 3 cases of patients with SNVs in OPHN1 and a phenotype that includes epilepsy/seizures. Carrier females may show milder phenotype.

Created: 14 Nov 2018, 4:27 p.m.

Comment on mode of inheritance: Note OMIM reports an XLR mode of inheritance. But evidence from PMIDs: 16221952, 29510240 suggest that carrier females can show phenotypic traits although in milder form.

Created: 14 Nov 2018, 4:26 p.m.

Comment on list classification: 3 cases of patients with SNVs in OPHN1 and a phenotype that includes epilepsy/seizures. Seizures not seen in every case.

Created: 14 Nov 2018, 4:12 p.m.

Associated with Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance in OMIM and MENTAL RETARDATION X-LINKED OPHN1-RELATED in Gene2Phenotype (confirmed).

Numerous SNV and microdeletions in OPHN1 reported in 11 families with individuals with X-linked mental retardation (PMID: 9582072, 9582072, 16221952, 16221952, 29510240). Both males and females affected. Seizures/epilepsy reported in PMID: 9582072 (2 sisters with deletion covering AR and OPHN1 genes), PMID: 16221952 (1 proband, nonsense mutation), PMID: 16221952 (deletion of exons 7-15), PMID: 29510240 (2 individuals from 2 unrelated families (B and D) with nonsense and missense variants).

Created: 14 Nov 2018, 3:59 p.m.

Green List (high evidence)

Seizures are part of the phenotype of this intellectual disability syndrome.

Created: 18 Aug 2018, 8:39 a.m.

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
Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance, MIM#300486

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