Early onset or syndromic epilepsy

Gene: PIGO

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)

AR hyperphosphatasia with mental retardation syndrome 2. Some patients have additional features incl seizures. Krawitz et al, 2012 - 2 sisters born of unrelated British parents (compound het for 2 PIGO mutations) and an unrelated girl with MR. The unrelated girl died of seizures at 22 months (compound het for two PIGO mutations) - in vitro functional expression studies done. Tanigawa et al, 2017 - new patients with PIGO mutation and also summarising against cases reported by Krawitz et al, 2012, Kuki et al, 2013, Nakamura et al, 2014 & Xue et al, 2016 - 7/11 had seizures from 6 families.

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

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hyperphosphatasia with mental retardation syndrome, 614749

Publications

• 22683086

Comment when marking as ready: Sufficient cases with compound heterozygous mutations in PIGO and 3 cases with seizures.

Created: 21 Nov 2018, 11:38 a.m.

Comment on publications: Further cases reported in PMIDs: 28900819 and 28337824

Created: 21 Nov 2018, 11:20 a.m.

Comment on list classification: Sufficient cases with compound heterozygous mutations in PIGO and 3 cases with seizures.

Created: 21 Nov 2018, 11:03 a.m.

PIGO is associated with Hyperphosphatasia with mental retardation syndrome 2 in OMIM and Gene2Phenotype (confirmed).

3 individuals from 2 families reported by Krawitz et al 2012 (PMID: 22683086). In family A two sisters are compound heterozygous for c.2869C>T and c.2361dup. In family B the affected individual is compound heterozygous c.2869C>T and c.3069+5G>A. The affected individual in family B presented with seizures.

Kuki et al 2013 (PMID: 24049131) reports case of 9 year old boy with deafness, tetralogy of Fallot, and Hirschsprung disease; showed muscular hypotonia and facial dysmorphism; and had short fingers with hypoplasia of the distal phalanges. At 1 year of age, he began to have intractable partial seizures. Two mutations were detected in PIGO, c.355C.T (p.Arg119Trp; NM_032634) and c.2497_2498del ,leading to a frameshift mutation, p.Ala834fs.

Nakamura et al 2014 (PMID: 24417746) reports 2 siblings with severe epileptic seizures, developmental delay, and mild elevation of ALP and compound heterozygous mutations in PIGO c.389C>A (p.Thr130Asn) and c.1288C>T (p.Gln430*).

Summary: >3 cases/families of compound heterozygous mutations in PIGO in patients with Hyperphosphatasia with mental retardation syndrome 2 and 3 cases with seizures.

Created: 21 Nov 2018, 11:01 a.m.

Green List (high evidence)

Seizures are part of the phenotype of this metabolic disorder.

Created: 18 Aug 2018, 10:43 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hyperphosphatasia with mental retardation syndrome 2, MIM#614749

Publications

• 28900819
• 28337824
• 24417746

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