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Early onset or syndromic epilepsy v2.491 PUM1 Sarah Leigh Tag for-review was removed from gene: PUM1.
Early onset or syndromic epilepsy v2.491 PUM1 Sarah Leigh commented on gene: PUM1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Early onset or syndromic epilepsy v2.490 PUM1 Sarah Leigh Source Expert Review Green was added to PUM1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Classified gene: PUM1 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Added comment: Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).
Early onset or syndromic epilepsy v2.200 PUM1 Arina Puzriakova Gene: pum1 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.199 PUM1 Arina Puzriakova Tag for-review tag was added to gene: PUM1.
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Classified gene: PUM1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 SNVs in at least 5 unrelated cases and CNVs spanning PUM1 in 9 cases. Supportive functional studies also reported.
Early onset or syndromic epilepsy v2.9 PUM1 Sarah Leigh Gene: pum1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.8 PUM1 Sarah Leigh Added comment: Comment on phenotypes: Global developmental delay;Intellectual disability;Seizures;Abnormality of the face;Ataxia;Cryptorchidism
Early onset or syndromic epilepsy v2.8 PUM1 Sarah Leigh Phenotypes for gene: PUM1 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism to Spinocerebellar ataxia 47 617931
Early onset or syndromic epilepsy v2.7 PUM1 Sarah Leigh Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Early onset or syndromic epilepsy v2.0 PUM1 Zornitza Stark reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474920, 25768905, 30903679, 31859446; Phenotypes: intellectual disability, epilepsy, Spinocerebellar ataxia 47, MIM# 617931; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.0 PUM1 Konstantinos Varvagiannis gene: PUM1 was added
gene: PUM1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PUM1 were set to 29474920; 30903679; 31859446
Phenotypes for gene: PUM1 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the face; Ataxia; Cryptorchidism
Penetrance for gene: PUM1 were set to unknown
Review for gene: PUM1 was set to GREEN
Added comment: 5 unrelated individuals with de novo pathogenic PUM1 variants have been reported in the literature. DD (5/5), ID (4/5 - relevant severity to the current panel), seizures (4/4 - absence/tonic-clonic, abnormal EEG) and variable other features (incl. facial dysmorphism, ataxia, cryptorchidism) appear to be part of the phenotype. 9 individuals with deletions spanning PUM1 and proximal genes presented similar features.

[1] PMID: 29474920 - Gennarino et al (2018)
[2] PMID: 30903679 - Bonnemason-Carrere et al (2019)
[3] PMID: 31859446 - Voet et al (2019) [with review of the literature]

SNVs in relevant individuals were identified by exome sequencing and were in all cases de novo.

Arg1147Trp was a recurrent variant reported in 3 unrelated subjects with ID and seizures (Refs 1,2,3 / NM_001020658.1:c.3439C>T). A nonsense variant was reported in an additional one with DD, ID, seizures and additional features (c.2509C>T / p.Arg837* - Ref3). One individual with a de novo missense variant (c.3416G>A / p.Arg1139Trp) with DD and ataxia, though without ID was reported in Ref1.

Details on 9 individuals with 0.3 - 5.6 Mb deletions spanning PUM1 and other genes are provided in Ref1. Features also included DD, ID, seizures, ataxia, etc.

Extensive initial investigations were reported for individuals in Refs 2 and 3 (various investigations incl. karyotype, SNP-array, targeted sequencing of OPHN1, KANSL1 or of a small panel of ID genes, biopsies and/or metabolic work-up) to rule out alternative causes. These only revealed a likely benign CNV and a GRIA3 SNV of uncertain significance in the case of an individual harboring the recurrent Arg1147Trp variant [Ref2].

Role of the gene (from OMIM):
Pumilio proteins, such as PUM1, negatively regulate gene expression by repressing translation of mRNAs to which they bind (Lee et al., 2016). A clinically significant PUM1 target is ataxin (ATXN1; 601556), mutation in which causes spinocerebellar ataxia-1 (SCA1; 601556).

Variant studies:
- Arg1147Trp was shown to be associated with normal PUM1 mRNA levels, but reduced (to ~43%) PUM1 protein levels in patient fibroblasts. ATXN1 mRNA and protein levels, as well as protein and/or mRNA levels of other PUM1 targets were shown to be increased (Ref1).
- In Ref1, in vitro transfection assays with wt or mt PUM1 were performed in HEK293T cells to evaluate repression of ATXN1 and E2F3. While overexpression of wt and Arg1147Trp were able to reduce ATXN1 and E2F3 levels, Arg1139Trp was not able to repress ATXN1 or E2F3.
- Upon overexpression in mouse hippocampal neurons, PUM1 missense mutations (among others Arg1139Trp and Arg1147Trp) were shown to alter neuronal morphology.

Overall haploinsufficiency is the proposed mechanism for the disorder for which the acronym PADDAS is used (Pumilio1-associated developmental disability, ataxia and seizure).

Milder mutations reducing PUM1 levels by 25% are associated with adult-onset ataxia without ID (PRCA or Pumilio1-related cerebellar ataxia) [Ref1].

Mouse models:
The role of PUM1 was first suggested in mouse models where Pum1 mutations were shown to lead to a SCA1-like phenotype (PMID cited : 12086639 - Watase et al 2002) further shown to be caused by increased Atxn1 mRNA and protein levels (PMID cited : 25768905 - Gennarino et al 2015).
The mouse model seems to recapitulate several of the features observed in affected individuals : Pum1 homozygous ko mice display among others hyperactivity, progressive cerebellar signs, spontaneous seizures as also observed in affected individuals (PMID cited : 25768905 - Gennarino et al 2015). Cryptorchidism was observed in 2 patients similar to testicular hypoplasia reported in Pum1 ko mice (PMID cited : 22342750 - Chen et al 2012).
- Heterozygous mice were evaluated in Ref1 with 69% or 75% exhibiting spontaneous seizures by the end of 30 or 35 wks respectively, with abnormal EEG activity already by 16 wks.

Additional individuals with PUM1 variants and a relevant phenotype of ID with or without seizures have been reported as part of the DDD study or as external submissions to Decipher and ClinVar :

https://decipher.sanger.ac.uk/search?q=PUM1#research-variants/results [ DDD4K.01387 participant ]
https://decipher.sanger.ac.uk/search?q=pum1#consented-patients/results [ external submission(s) ]
https://www.ncbi.nlm.nih.gov/clinvar/variation/431110/ [ splice-site variant in an individual with ID submitted prior to the 1st publication on the disorder ]
Sources: Literature