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Intellectual disability

Gene: DHPS

Green List (high evidence)

DHPS (deoxyhypusine synthase)
EnsemblGeneIds (GRCh38): ENSG00000095059
EnsemblGeneIds (GRCh37): ENSG00000095059
OMIM: 600944, Gene2Phenotype
DHPS is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Comment on list classification: Expert review by Konstantinos Varvagiannis on DHPS. Ganapathi et al. (PMID : 30661771) 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).

DHPS has a relevant phenotype associated in OMIM and is probable in G2P as "Disease: Neurodevelopmental Disorder of Hypusination", but no phenotypes have been assigned to the entry.

Overall sufficient (>3) unrelated cases of developmental delay in patients with DHPS variants, for inclusion on this panel.
Created: 20 May 2019, 10:35 a.m. | Last Modified: 25 Jun 2019, 3:54 p.m.
Panel Version: 0.194

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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).
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DHPS is not associated with any phenotype in G2P, nor in OMIM.
This gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories.
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As a result, DHPS can be considered for inclusion in this panel as green (or amber).
Sources: Literature
Created: 20 Jan 2019, 11:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; EEG abnormality; Behavioral abnormality; Abnormality of head or neck

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review
Phenotypes
  • Abnormality of head or neck
  • Seizures
  • Abnormal muscle tone, Global developmental delay, Intellectual disability, Seizures, EEG abnormality, Behavioral abnormality, Abnormality of head or neck
  • EEG abnormality
  • Behavioral abnormality
  • Abnormal muscle tone
  • Intellectual disability
  • Global developmental delay
OMIM
600944
Clinvar variants
Variants in DHPS
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to DHPS. Source Expert Review was added to DHPS. Added phenotypes Abnormal muscle tone, Global developmental delay, Intellectual disability, Seizures, EEG abnormality, Behavioral abnormality, Abnormality of head or neck 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)

20 Jan 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: DHPS was added gene: DHPS was added to Intellectual disability. 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