Early onset or syndromic epilepsy

Gene: PIGG

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 Mental retardation 53 (MRT53) - early onset seizures seen in most patients. Makrythanasis et al, 2016 - 5 patients from 3 unrelated families all with early-onset seizures. In 4 patients from 2 unrelated families (2 sets of sibs) - 2 diff hom missense variants and the patient from the third family was a compund het for a missense and a large del encompassing the gene. Functional work - loss of PIGG function. Zhao et al, 2017 - 2 siblings both with early-onset seizures - hom nnsense variant - functional evidence suggest pathogenic.

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
Mental retardation, 616917

Publications

• 26996948

Comment when marking as ready: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 3 variants, plus one 2.4mb deletion encompassing the PIGG gene reported in three unrelated cases.

Created: 7 Nov 2018, 1:31 p.m.

Green List (high evidence)

PMID: 26996948 reports on 5 individuals from 3 families, with biallelic pathogenic variants in PIGG.

Individuals from first family, were born to consanguineous parents from Egypt and were homozygous for a stopgain variant [p.(Gln310*)]. The patient from the second family had a rare missense SNV [p.(Arg669Cys)] and a de novo microdeletion affecting PIGG on her other allele. In the third family (consanguineous parents from Pakistan), two affected sibs were found to be homozygous for a splice variant.

The phenotype consisted of hypotonia, early-onset seizures and intellectual disability. Ataxia was an additional feature in one of the families.

Seizures, were observed in most of patients but do not appear to be a universal feature as they were absent in one of the sibs from the third family (10 years of age), while the other had a single episode by the age of 12 years.

In vitro testing of lymphoblastoid cell lines (generated from individuals from the 1st and 3rd family) indicated that the variants abolished completely the function of PIGG, whereas the surface level of GPI anchored proteins was normal. //

PMID: 28581210 describes the phenotype of 2 sibs from Palestine, homozygous for a stopgain variant [p.(Trp547*)]. Hypotonia, feeding difficulties, severe non-progressive ataxia (with cerebellar hypoplasia), intellectual disability and seizures were common features. Differences in severity and/or additional features might be explained by other homozygous variants (the girl had a concurrent diagnosis of MCAD deficiency).

The authors demonstrated that the PIGG transcript levels were significantly lower (approximately half) in the two siblings compared to their parents, while the transcripts with the mutation in the heterozygous parents were very low due to nonsense-mediated decay.

Patient fibroblasts showed decreased surface level of GPI-anchored proteins, in contrast with what was noted in lymphoblastoid cells in the previous study. //

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review

Created: 15 Oct 2018, 2:51 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
# 616917. MENTAL RETARDATION, AUTOSOMAL RECESSIVE 53; MRT53

Publications

• 26996948
• 28581210