Intellectual disabilityGene: PIGP
Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and Amber rating on the Genetic epilepsy syndromes panel. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Created: 24 Oct 2019, 9:29 a.m. | Last Modified: 24 Oct 2019, 9:29 a.m.
Panel Version: 2.1071
Summary of cases (see Konstantinos Varvagiannis' review for details). 2 independent cases reported in OMIM, plus a third case from LOVD database:
Johnstone et al., 2017 (PMID:28334793) report a pair of siblings with compound het PIGP variants (p.Met25Thr and p.Glu153AsnFs*34). Both children presented with seizures, hypotonia, and profound global developmental delay.
Krenn et al.,2019 (PMID:31139695) report a Polish girl with infantile seizures, hypotonia, severe developmental dely and feeding difficulties. She had a frameshift Glu153Asnfs*34 variant in PIGP.
The third case reported by Konstantinos comes from LOVD, and is a homozygous pathogenic frameshift variant p.(Glu129Argfs*7): https://databases.lovd.nl/shared/variants/0000500090#00016155. The full phenotype isn't listed.
Created: 20 Sep 2019, 12:31 p.m. | Last Modified: 20 Sep 2019, 12:31 p.m.
Panel Version: 2.1023
Please consider upgrading this gene to Green.
In a recent study, Vetro et al. (2020 - https://doi.org/10.1212/NXG.0000000000000387) identified 4 additional affected individuals with severe EIEE, belonging to a large inbred family. Following extensive genetic investigations (all of which were non-diagnostic) these subjects were found to harbor in homozygosity the frameshift variant also reported in the 2 previous studies (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34). Reduced expression of the GPI-anchor protein CD16 was demonstrated in granulocytes of affected individuals.
Created: 12 Jan 2020, 7:14 p.m. | Last Modified: 12 Jan 2020, 7:16 p.m.
Panel Version: 3.0
Johnstone et al. (2017 - PMID: 28334793) report on 2 sibs born to non-consanguineous parents of French-Irish ancestry. Both presented with seizures (onset at the age of 2 and 7 weeks respectively), hypotonia and profound DD. Other features included CVI and feeding difficulties. Extensive metabolic testing as well as prior genetic testing (ARX, STXBP1, MECP2, aCGH) in the family were non-diagnostic. WES suggested the presence of 2 PIGP variants with Sanger sequencing used for confirmation and segregation studies.
PIGP encodes a subunit of the enzyme that catalyzes the first step of glycophosphatidylinositol (GPI) anchor biosynthesis. Mutations in other genes whose proteins are in complex with PIGP (PIGA, PIGC, PIGQ, PIGY, DPM2) lead to similar phenotypes. The phenotype overall was also overlapping with the inherited GPI deficiencies (belonging to the broader group of CDGs).
PIGP has 2 isoforms, which differ by 24 amino acids due to utilization of alternative start codons [corresponding to NM_153681.2 (158 aa) and NM_153682.2 (134 aa)].
The variants identified affected both transcripts with the first SNV leading either to loss of the start codon (NM_153682.2:c.2T>C - p.Met1Thr) or to substitution of a methionine at position 25(NM_153681.2:c.74T>C;p.Met25Thr). The second variant led to frameshift in the last exon of both transcripts predicting a longer protein product (NM_153681.2:c.456delA / p.Glu153AsnfsTer34 or NM_153682.2:c.384delA / p.Glu129AsnfsTer34).
Overall extensive studies demonstrated decreased levels of PIGP mRNA in patient fibroblast, decreased amounts of mutant protein in transfected HEK293 cells. The decreased levels of GPI-APs further supported the effect of variants :
- mRNA levels in patient fibroblasts were reduced compared to controls. Conclusions could not be drawn from Western blot, since no antibodies could specifically detect PIGP. HEK293 cells transfected of mt or wt HA-tagged PIGP cDNA led to undetectable amounts for the first variant (both M1T/M25T) and a protein product of increased molecular weight for the frameshift one.
- Flow cytometry of patient granulocytes indicated reduced signal of CD16 (a GPI-anchored protein) and FLAER (binding directly to the GPI anchor).
- Reduced levels of GPI-APs were also observed in PIGP deficient HAP1 cells transfected with either wt, or mutant PIGP cDNA (of both isoforms for the M1T/M25T or isoform 2 for the frameshift mutation).
Krenn et al. (2019 - PMID: 31139695) described a patient born to non-consanguineous Polish parents. Features were highly similar to those reported by Johnstone et al. and incl. intractable infantile seizures (onset at 7m), hypotonia, severe DD and feeding difficulties. Metabolic work-up failed to identify an alternative diagnosis. WES revealed homozygosity for the frameshift variant reported by Johnstone et al. Sanger sequencing confirmed the variant and carrier state in both parents. Identified ROH of less than 7 Mb in the WES data, suggested a founder mutation rather than unreported consanguinity. The variant is present 9 times in gnomAD (AF of 3.2e-5 / no homozygotes). Flow cytometry of patient granulocytes, revealed markedly reduced expression of GPI-APs (CD157, CD59, FLAER) compared to parents/controls.
ALP was normal in all aforementioned individuals (probably in line with PIGP being involved in the 1st step of the GPI anchor biosynthesis).
A further individual with phenotype of EIEE-55;GPIBD-14 is reported in LOVD [Individual #00246132]. This individual, born to consanguineous parents, was tested by WES and found to be homozygous for a frameshift variant, also affecting the last exon in both transcripts (NM_153681.2:c.384delA (p.Glu129ArgfsTer7) / NM_153682.2:c.312delA (p.Glu105ArgfsTer7). This was probably in agreement with segregation studies according to the respective entry. The specific variant is reported as pathogenic [variant ID #0000500090].
?Epileptic encephalopathy, early infantile, 55 (MIM 617599) is the corresponding phenotype in OMIM. There is no relevant G2P entry.
PIGP is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
As a result, PIGP can be considered for inclusion in the ID/epilepsy panels probably as green (3 individuals, role of the gene and similarity to other inherited GPI deficiencies, extensive supporting studies) or amber.
(Please consider inclusion in other possibly relevant panels eg. CDGs, etc).
Created: 7 Sep 2019, 10:41 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
Variants in this GENE are reported as part of current diagnostic practice
Gene: pigp has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: PIGP were changed from Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment to ?Epileptic encephalopathy, early infantile, 55, 617599; Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment
gene: PIGP was added gene: PIGP was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PIGP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGP were set to 28334793; 31139695 Phenotypes for gene: PIGP were set to Generalized hypotonia; Global developmental delay; Seizures; Intellectual disability; Feeding difficulties; Cortical visual impairment Penetrance for gene: PIGP were set to Complete Review for gene: PIGP was set to GREEN gene: PIGP was marked as current diagnostic