Early onset or syndromic epilepsy

Gene: P4HTM

I don't know

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Green List (high evidence)

AR HIDEA. Rahhikkala et al, 2019 (30940925) - 7 patients from 4 unrelated families with HIDEAA syndrome and reviewed the large Finnsih family orig reported by Kaasinen et al, 2014. Moust had seizures (10/13) assoc with EEG abnormalities mainly multifocal spikes. One patient didn't have overt seizures but did have EEG abnormal. 5 diff hom/compound het variants reported in aff members in these 5 families. In vitro functional studies of three of these vairants showed that they caised a significant decrease in the amount of soluble protein compared to wild type. These findings suggest that the mutation cause structutral abnormalities and imporoper folding of the protein resulting in a LOF.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Gene given a Green expert review by Konstantinos Varvagiannis on Rahikkala et al. (2019 - PMID: 30940925) who reports on 13 individuals from 5 families with biallelic pathogenic P4HTM variants.
From the 7 individuals identified 6 individuals from 4 families had undergone trio sequencing one affected sibling had deceased before being sequenced.
6 of these individuals are from a large consanguineous family from Finland and were previously reported by the same group (Kaasinen et al. - PMID: 25078763).

Common phenotypes included Hypotonia, DD and ID and Eye Abnormalities, the reason why the acronym HIDEA is suggested for the disorder. P4HTM is not in OMIM or G2P. However a consistent phenotype is seen throughout the individuals. Epilepsy is seen in 10 out 13 of the individual. There is functional work to support too.

Therefore as there are sufficient variants (5) from unrelated individuals P4HTM can be rated as Green.

Created: 26 Jun 2019, 2:04 p.m. | Last Modified: 10 Jul 2019, 8:36 a.m.

Panel Version: 0.68

Green List (high evidence)

Gene added in the ID panel. Epilepsy is a feature of the disorder.
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Rahikkala et al. (2019 - PMID: 30940925) report on 13 individuals from 5 families with biallelic pathogenic P4HTM variants. 6 of these individuals from a large consanguineous family from Finland were previously reported by the same group, although studies at the time had revealed a 11.5 Mb region of homozygosity with 3 genes within this interval considered to be candidate for the patients' phenotype (P4HTM, TKT, USP4) [Kaasinen et al. - PMID: 25078763].

Common features included Hypotonia (13/13), DD and ID (the latter present in 12/13 individuals with appropriate age for evaluation) and Eye Abnormalities, reason why the acronym HIDEA is suggested for the disorder. Epilepsy was observed in 10 individuals (10/13). Hypoventilation, sleep apnea and dysautonomia were additional features reported.

Muscle biopsies from 4 individuals had variable findings suggestive of disruption of normal mitochondrial function.

Finnish patients were homozygous for a SNV - possibly a founder variant in this population - predicted to lead to a missense change in the canonical transcript (NM_177938.2:c.1073G>A) but causing an in-frame loss of the complete exon 6 of another transcript (NM_177939.2).

The latter transcript (encoding a 502 aa protein) is the prevalent one in fibroblasts/myoblasts instead of the canonical one (563 aa). It is not known whether the canonical transcript is the prevalent in brain tissue although northern blot analysis in a previous study suggested presence of a 2.3 kb mRNA in brain instead of a 1.8 kb observed in other tissues, a finding which may be suggestive of expression of the canonical transcript. [Reviewer's note: In gnomAD based on the pext values from the GTEx, the noncanonical transcript appears to be prevalent in brain regions - https://gnomad.broadinstitute.org/gene/ENSG00000178467]

All variants reported affected both transcripts. All 5 variants have been submitted to LOVD ( https://databases.lovd.nl/shared/variants/P4HTM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22 - first author appearing as the submitter).

Overexpression of wt and 3 mutants (His161Pro, Gln352*and Exon6del) in insect cells followed by analysis with SDS-PAGE and western blot revealed severly reduced/abolished fraction of soluble protein for the 3 studied variants suggesting improper protein folding.

Knockout of the gene in mice leads to retinal defects and/or visual impairment in line with eye abnormalites (nystagmus, strabismus, achromic retinal fundi or cortical blindness) being a prominent feature in affected individuals. Mouse studies suggest that this gene is also important for renal function, although kidney problems were not reported in any affected individual.

Overall loss-of-function is suggested to be the underlying mechanism.

P4HTM is not associated with any phenotype in OMIM, nor in G2P. This gene is not (at least commonly) included in gene panels for ID offered by diagnostic laboratories.

As a result P4HTM can be considered for inclusion in the ID and epilepsy panels probably as green (several affected individuals) or amber.
Sources: Literature

Created: 7 Apr 2019, 4:39 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Central hypotonia; Muscular hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Hypoventilation; Sleep apnea; Dysautonomia

Publications

• 30940925