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| Intellectual disability v2.978 | P4HTM |
Catherine Snow Source Expert Review Green was added to P4HTM. Source Expert Review was added to P4HTM. Added phenotypes Central hypotonia, Muscular hypotonia, Global developmental delay, Intellectual disability, Seizures, Abnormality of the eye, Hypoventilation, Sleep apnea, Dysautonomia for gene: P4HTM Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability v2.798 | P4HTM |
Konstantinos Varvagiannis gene: P4HTM was added gene: P4HTM was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: P4HTM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: P4HTM were set to 30940925; 25078763 Phenotypes for gene: P4HTM were set to Central hypotonia; Muscular hypotonia; Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Hypoventilation; Sleep apnea; Dysautonomia Penetrance for gene: P4HTM were set to Complete Review for gene: P4HTM was set to GREEN Added comment: 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 in 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 - the 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, degree of ID relevant) or amber. Sources: Literature |
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