Early onset or syndromic epilepsy

Gene: ARX

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)

Polyalanine tract expansion (exon 2) in addition to missense, nonesense, frameshift variants etc. phenotypic spectrum of disorders caused by a variant in the ARX gene, comprising a nearly continuous series of developmental disorders ranging from MR (Partington syndrome), hrdanencephaly and lissencephaly (LISX2), Proud syndrome and XLR EIEE1 - these final 2 are both associated with seizures. Males with ARX mutations are often more severely affected, female mutation carriers may also be affected. Lots of reported cases - OMIM and HGMD Pro. Functional studies - Shoubridge et al, 2012.

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, biallelic mutations in females

Phenotypes
Epileptic encephalopathy, early infantile, 1, 308350; Hydranencephaly with abnormal genitalia,300215 ; Lissencephaly, X-linked 2, 300215; Mental retardation, X-linked 29, 300419; Partington syndrome,309510; Proud syndrome, 300004

Publications

• 17490853
• 17668384
• 18462864

Comment on mode of inheritance: The revised mode of inheritance fits with gene2phenotype of hemizygous inheritance for this disorder.

Created: 17 Dec 2015, 12:32 p.m.

Comment on mode of inheritance: Discussion with reviewer determined that females require two mutations to develop this disorder (X-linked recessive).

Created: 17 Dec 2015, 11:43 a.m.

Green List (high evidence)

Where females manifest it would be due to x-skewing. Is this the right option?

Created: 12 Nov 2015, 1:50 p.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
Epileptic encephalopathy, early infantile, 1; Lissencephaly, X-linked 2; Mental retardation, X-linked, with or without seizures, ARX-related; Partington syndrome; Proud syndrome

Publications

• Tsurusaki et al (2002) Nature 30: 441-445
• Kato et al (2004) Hum Mut 23: 147-159
• Bienvenu et al (2002) Hum Mol Genet 11(8): 981-991
• Partington et al (1998) Am J Med Genet 30: 251-262
• Kato et al (2004) Hum Mut 23: 147-159

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

Green List (high evidence)

Where females manifest it would be due to x-skewing. Is this the right option?

Created: 12 Nov 2015, 1:14 p.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
Epileptic encephalopathy, early infantile, 1; Lissencephaly, X-linked 2; Mental retardation, X-linked, with or without seizures, ARX-related; Partington syndrome; Proud syndrome

Publications

• Tsurusaki et al (2002) Nature 30: 441-445
• Kato et al (2004) Hum Mut 23: 147-159
• Bienvenu et al (2002) Hum Mol Genet 11(8): 981-991
• Partington et al (1998) Am J Med Genet 30: 251-262
• Kato et al (2004) Hum Mut 23: 147-159

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

Green List (high evidence)

Where females manifest it would be due to x-skewing. Is this the right option?

Created: 12 Nov 2015, 1:04 p.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
Epileptic encephalopathy, early infantile, 1; Lissencephaly, X-linked 2; Mental retardation, X-linked, with or without seizures, ARX-related; Partington syndrome; Proud syndrome

Publications

• Tsurusaki et al (2002) Nature 30: 441-445
• Kato et al (2004) Hum Mut 23: 147-159
• Bienvenu et al (2002) Hum Mol Genet 11(8): 981-991
• Partington et al (1998) Am J Med Genet 30: 251-262
• Kato et al (2004) Hum Mut 23: 147-159

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

Green List (high evidence)

Where females manifest it would be due to x-skewing. Is this the right option?

Created: 12 Nov 2015, 12:26 p.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
Epileptic encephalopathy, early infantile, 1; Lissencephaly, X-linked 2; Mental retardation, X-linked, with or without seizures, ARX-related; Partington syndrome; Proud syndrome

Publications

• Tsurusaki et al (2002) Nature 30: 441-445
• Kato et al (2004) Hum Mut 23: 147-159
• Bienvenu et al (2002) Hum Mol Genet 11(8): 981-991
• Partington et al (1998) Am J Med Genet 30: 251-262
• Kato et al (2004) Hum Mut 23: 147-159

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