Genetic epilepsy syndromesGene: DHPS
Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:20 a.m. | Last Modified: 9 Sep 2019, 10:20 a.m.
Panel Version: 1.314
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
AR NEDSSWI. Ganapathi et al, 2019 (30661771)- 5 patients including 2 sibs (all european descent). 4 patients had variable clinical seizures and 1 had staring spells. Compound het mutations identified. All patients had the same het missense variant, N173S on one allele and either a splice site, in frame del or point mutation disrupting the initiation codon on the other. Haplotypye analysis suggested common ancestor for N173S variant in 3 of the families. In vitro functional expression studies of the purified enzyme in E coli showed that N173S and Y305_I306del variants, both of which affected highly conserved AA, had decreased enzyme activity manifest as impaired biosynthesis of deoxyhypusine compared to wt. Knock out mouse studies done on this gene - Templin et al, 2011 (21389784) and Nishimura et al, 2012 (21850436).
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
Expert review by Konstantinos Varvagiannis on DHPS. Ganapathi et al. (PMID : 30661771) report on 5 individuals from 4 unrelated families with compound heterozygous variants in DHPS. All families have family trio sequencing performed.
DHPS has a relevant phenotype associated in OMIM and is probable in Gene2Phenotype and phenotype of DD, and hypotonia is consistent throughout. All five individuals have DD before any seizures. Seizures occur in 4/5 cases and all individuals are reported to have EEG abnormalities.
There are a sufficient number of unrelated families to classify DHPS as Green.
Created: 24 Jun 2019, 4:21 p.m. | Last Modified: 25 Jun 2019, 3:53 p.m.
Panel Version: 0.17
Ganapathi et al. (doi.org/10.1016/j.ajhg.2018.12.017 - PMID : NA) report on 5 individuals from 4 unrelated families with biallelic pathogenic variants in DHPS.
The phenotype consisted of DD/ID (5/5), tone abnormalities (hypotonia/hypertonia/spasticity - 5/5), seizures (5/5 - in one case though unclear staring spells) with EEG abnormalities (5/5). Additionally most individuals displayed behavioral issues, or some common facial features.
Several other disorders had been ruled prior to the diagnosis, in all cases by exome sequencing.
All individuals harbored a specific missense variant (c.518A>G or p.Asn173Ser) in trans with various other variants incl. a splice site mutation (c.1014+1G>A), an in-frame deletion of 2 amino acids (c.912_917delTTACAT or p.Tyr305_Ile306del) or a variant abolishing the translation initiation codon (c.1A>G or p.Met1?) [All variants using NM_001930.3 as a reference].
Deoxyhypusine synthase (encoded by DHPS) is an enzyme participating in the first step of hypusine synthesis, an amino-acid which is specific to eukaryotic initiation factor 5A (eIF5A) and its homolog (eIF5A2).
eIF5A, its hypusinated form and DHPS have all been previously implicated in cellular proliferation/differentiation. eIF5A has also been proposed to be a mRNA translation elongation factor. A role of eIF5A in neuronal growth and survival has been proposed previously (all ref. in present article).
Neither eIF5A, nor DHPS or DOHH (an enzyme required for the second step of hypusination) have been associated to any disorders previously. Mutations in genes encoding other eukaryotic elongator factors (eg. EEF1A2, EEF2) have been associated with neurodevelopmental disorders.
Concerning the DHPS variants reported:
cDNA studies suggested that the c.1014+1G>A variant is translated but results in aberrant splicing and truncation of the protein before its active site.
The in-frame deletion as well as the missense variant were shown to have absent or partial (20%) enzyme activity in vitro respectively compared to wild-type (following expression in E.coli BL21(DE3) cells).
In line with this, reduced hypusination of eIF5A was observed for these 2 variants when compared to wild-type DHPS, upon co-transfection of constructs overexpressing DHPS (wt or mut.) and eIF5A in HEK293T cells.
Absence of homozygous DHPS LoF variants in population databases might suggest that complete deficiency is incompatible with normal embryonic development. Mice heterozygous for Dhps deletion do not demonstrate severe phenotypes, though homozygosity is embryonically lethal (PMIDs: 21389784, 21850436).
DHPS is not associated with any phenotype in G2P, nor in OMIM.
As a result, DHPS can be considered for inclusion in this panel as green (or amber).
Created: 20 Jan 2019, 11:36 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck
Source Wessex and West Midlands GLH was added to DHPS.
Source NHS GMS was added to DHPS.
Source Expert Review Green was added to DHPS. Source Expert Review was added to DHPS. Added phenotypes Abnormality of head or neck; Seizures; EEG abnormality; Behavioral abnormality; Abnormal muscle tone; Intellectual disability; Global developmental delay for gene: DHPS Publications for gene DHPS were changed from 21389784; 21850436 to 21389784; 30661771; 21850436 Rating Changed from No List (delete) to Green List (high evidence)
gene: DHPS was added gene: DHPS was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHPS were set to 21389784; 21850436 Phenotypes for gene: DHPS were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck Penetrance for gene: DHPS were set to Complete Review for gene: DHPS was set to GREEN