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Early onset or syndromic epilepsy v2.518 PABPC1 Konstantinos Varvagiannis gene: PABPC1 was added
gene: PABPC1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PABPC1 were set to 35511136
Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures
Penetrance for gene: PABPC1 were set to unknown
Review for gene: PABPC1 was set to AMBER
Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1.

Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible.

All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del).

Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date).

PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory.

To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes.

Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect.

While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence.

Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding.

In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules.

In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below).

Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype.

Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed.

Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194).

Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia).

Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants).
Sources: Literature
Early onset or syndromic epilepsy v1.191 TBL1XR1 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBL1XR1.
Early onset or syndromic epilepsy v1.190 TBL1XR1 Rebecca Foulger Source NHS GMS was added to TBL1XR1.
Early onset or syndromic epilepsy v1.189 TBL1XR1 Rebecca Foulger edited their review of gene: TBL1XR1: Added comment: 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. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 TBL1XR1 Tracy Lester reviewed gene: TBL1XR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25102098; Phenotypes: Mental retardation autosomal dominant 41, 616944, Pierpont syndrome, 602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v0.651 TBL1XR1 Rebecca Foulger Marked gene: TBL1XR1 as ready
Early onset or syndromic epilepsy v0.651 TBL1XR1 Rebecca Foulger Gene: tbl1xr1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.651 TBL1XR1 Rebecca Foulger Classified gene: TBL1XR1 as Green List (high evidence)
Early onset or syndromic epilepsy v0.651 TBL1XR1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Confirmed DD-G2P gene for Pierpont and mental retardation, both of which can present with seizures. Seizures reported in at least 3 patients (PMID:25102098, PMID:30365874 and PMID:9450851-original patient). Burkitt Wright, 2011 (PMID:21834056) also reports that "Seizures, in particular absence seizures, have been reported in several [Pierpont] patients. While they are clearly not universal, it currently appears that epilepsy may be sufficiently more common in children with Pierpont syndrome to be considered a feature of the condition". Therefore reasonable to include TBL1XR1 on the diagnostic panel.
Early onset or syndromic epilepsy v0.651 TBL1XR1 Rebecca Foulger Gene: tbl1xr1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.650 TBL1XR1 Rebecca Foulger Publications for gene: TBL1XR1 were set to
Early onset or syndromic epilepsy v0.649 TBL1XR1 Rebecca Foulger Mode of inheritance for gene: TBL1XR1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v0.648 TBL1XR1 Rebecca Foulger Phenotypes for gene: TBL1XR1 were changed from to Mental retardation, autosomal dominant 41, 616944; Pierpont syndrome, 602342
Early onset or syndromic epilepsy v0.647 TBL1XR1 Rebecca Foulger commented on gene: TBL1XR1: Previously reported individuals reported by Burkitt Wright, 2011 (PMID:21834056) include the initial patient reported by Pierpont et al 1998 (PMID:9450851) who had grand mal seizures from age 5.
Early onset or syndromic epilepsy v0.647 TBL1XR1 Rebecca Foulger commented on gene: TBL1XR1: PMID:30365874 (Lemattre et al 2018) report a Caucasian boy (Patient 1) with a seizure disorder with both myoclonic and focal seizures that began age 10. Her harboured a de novo heterozygous missense variant (NM_024665.4:c.974G>A, p.Cys325Tyr) in TBL1XR1. Their second unrelated patient also had a missense TBL1XR1 variant but never had seizures.
Early onset or syndromic epilepsy v0.647 TBL1XR1 Rebecca Foulger commented on gene: TBL1XR1: In a 5-year-old Japanese girl with autosomal dominant mental retardation-41 (MRD41; 616944), Saitsu et al. (2014, PMID:25102098) identified a de novo heterozygous transition (c.209G-A, NM_024665.4) in the TBL1XR1 gene (G70D). The patient developed infantile spasms at age 5 months.
Early onset or syndromic epilepsy v0.647 TBL1XR1 Rebecca Foulger commented on gene: TBL1XR1
Early onset or syndromic epilepsy TBL1XR1 Zornitza Stark reviewed gene: TBL1XR1
Early onset or syndromic epilepsy TBL1XR1 Sarah Leigh Added gene to panel