Early onset or syndromic epilepsy

Gene: PIGQ

Comment on phenotypes: According to Joanna Peas-Welch (OMIM), Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) will replace Epileptic encephalopathy, early infantile, 77, 618548 as the name for this phenotype (12/11/2020).

Created: 17 Nov 2020, 11:19 a.m. | Last Modified: 17 Nov 2020, 11:19 a.m.

Panel Version: 2.218

Green List (high evidence)

Homozygous or compound heterozygous mutations in PIGQ cause Epileptic encephalopathy, early infantile, 77 (MIM #618548).

Johnstone et al (2020 - PMID: 32588908) describe the phenotype of 7 children (from 6 families) with biallelic PIGQ pathogenic variants. The authors also review the phenotype of 3 subjects previously reported in the literature (by Martin et al, Alazami et al, Starr et al - respective PMIDs: 24463883, 25558065, 31148362).

Affected individuals displayed severe to profound global DD/ID and seizures with onset in the first year of life. There were variable other features incl. - among others - genitourinary, cardiac, skeletal, ophthalmological anomalies, gastrointestinal issues. Within the cohort there was significant morbidity/mortality.

PIGQ encodes phosphatidylinositol glycan anchor biosynthesis class Q protein, playing a role (early) in the biosynthesis of the GPI-anchor. Several genes in the GPI biosynthesis pathway cause multi-system disease with DD/ID and seizures. Flow cytometry has been used in individuals with PIGQ-related disorder. Serum ALP was elevated in some (4) although - as the authors comment - elevations are more typical in disorders affecting later steps of GPI biosynthesis.

More than 10 variants have been reported to date (missense / pLoF).

Overall PIGQ can be considered for green rating in both ID and epilepsy gene panels.

Created: 3 Aug 2020, 10:36 p.m. | Last Modified: 3 Aug 2020, 10:36 p.m.

Panel Version: 2.133

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 77 (MIM #618548)

Publications

• 32588908
• 24463883
• 25558065
• 31148362

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: Alison Callaway and John Taylor. 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)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Glycosylphosphatidylinositol biosynthesis defect

Publications

• 24463883

Comment on list classification: 3 cases plus some functional data.

Created: 19 Jun 2019, 9:30 a.m.

Not associated with a phenotype in OMIM although one variant from Martin et al 2014 is noted.
In Gene2Phenotype there is a possible association with SEVERE EARLY-ONSET EPILEPSY (ballelic)

PMID: 24463883 - Martin et al 2014 - 1 case. A child of West African origin, had severe early-onset epilepsy with a burst-suppression EEG, consistent with Ohtahara Syndrome. A homozygous A-to-G transition in intron 2 of the PIGQ gene (c.690-2A-G), resulting in the skipping of exon 3 and an in-frame deletion of 44 amino acids. The mutation was confirmed by Sanger sequencing and segregated with the disorder in the family. Some functional data: transfection of the mutation into PIGQ-deficient CHO cells did not restore GPI-anchored protein expression as efficiently as wildtype, and expression of the mutant protein was decreased compared to wildtype, consistent with a loss-of-function effect. The patient had onset of refractory seizures at age 4 weeks. 

PMID: 25558065 - Alazami et al 2015 - 1 case with consanguineous parents listed in Table S1 with a variant in PIGQ (NM_004204.3:c.619C>T:p.R207*) and Intractable seizure, developmental delay, and optic atrophy.

PMID: 31148362 - Starr et al 2019 - describe a patient with a multisystem disorder including epilepsy. He was compound heterozygous for two variants in PIGQ; a maternal frameshift mutation c.968_969delTG (p.L323Pfs*119) resulting in premature protein truncation and a paternal origin in‐frame deletion c.1199_1201delACT (p.Y400del).  The authors state that the three patients support evidence for a new syndrome—PIGQ‐related GPI‐AP biosynthesis deficiency syndrome.

The recent Deb Pal review is referencing the Martin et al paper.

Summary: There are now 3 cases of patients with plausible disease causing variants in this gene and disorders that have epilepsy as part of the phenotype.

Created: 19 Jun 2019, 9:29 a.m.

Red List (low evidence)

Amplexa CHE-114 epilepsy panel

Created: 21 Feb 2019, 2:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epilepsy; Ohtahara syndrome

Publications

• 24463883

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

I don't know

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

Created: 11 Dec 2018, 2:34 p.m.

Comment on phenotypes: added phenotype from expert review

Created: 11 Dec 2018, 2:28 p.m.

Comment on publications: added publication suggested by external reviewer

Created: 11 Dec 2018, 2:23 p.m.

Transferred over Review by Alistair Pagnamenta (University of Oxford) 5 Dec 2018, 12:39 p.m.
from Panel version: 1.147 Panel name: Epileptic encephalopathy.

Alazami et al identified a patient with "Intractable seizure, developmental delay and optic atrophy" and homozygous c.619C>T; p.Arg207Ter variant in this gene. See www.ncbi.nlm.nih.gov/clinvar/variation/183339/ and supplemental data for PMID: 25558065. I'm not sure if this is sufficient to upgrade to amber but nevertheless worth highlighting as there is phenotypic overlap with patient described in Martin et al and none of the other reviews mention this study.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intractable seizures; developmental delay; optic atrophy

Publications
PMID: 25558065

Created: 11 Dec 2018, 2:22 p.m.

Red List (low evidence)

Publications

• Martin et al (2014) Hum Mol Genet 23(12).3200-3211

Red List (low evidence)

Publications

• Martin et al (2014) Hum Mol Genet 23(12).3200-3211

Red List (low evidence)

Publications

• Martin et al (2014) Hum Mol Genet 23(12).3200-3211

Red List (low evidence)

Publications

• Martin et al (2014) Hum Mol Genet 23(12).3200-3211

Gene added in expert review of the panel by Richard Scott (Genomics England), Manju Kurian (UCL-Institute of Child Health), Natalie Trump (NHS - Great Ormond Street Hospital), Amy McTague (UCL Institute of Child Health).

Created: 12 Nov 2015, 4:18 p.m.