Early onset or syndromic epilepsy
Gene: OPHN1
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
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
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.
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
Source Wessex and West Midlands GLH was added to OPHN1.
Source NHS GMS was added to OPHN1.
Zornitza Stark: Seizures are part of the pheno
Gene: ophn1 has been classified as Green List (High Evidence).
Mode of inheritance for gene: OPHN1 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Gene: ophn1 has been classified as Green List (High Evidence).
Phenotypes for gene: OPHN1 were changed from to Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance 300486; MENTAL RETARDATION X-LINKED OPHN1-RELATED
Publications for gene: OPHN1 were set to
Expert Review Amber was added to OPHN1. Panel: Genetic Epilepsy Syndromes
OPHN1 was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
OPHN1 was created by Sarah Leigh