Expanding the Phenotypic Spectrum Associated with DPH5-Related Diphthamide Deficiency

Abstract

Background/objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis.

Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools.

Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype-phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome.

Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes.

Keywords: DPH5; diphtamide deficiency; neurodevelopmental disorder; ribosomopathy.

Figure 1

DPH5 and the diphthamidation pathway. DPH5 is important in diphthamide synthesis, which is important in the regulation of protein translation in general, particularly in selenoprotein translation and hence oxidative stress balance, although other pathways may be feasible but are not known to date. In the top left, DPH5 catalyzes the diphthamidation of eEF2 (black arrow denotes the conversion of non-diphthamidated to diphthamidated eEF2 through DPH5 activity). In the right panel, diphthamidated eEF2 facilitates efficient protein translation (indicated by grey arrows representing sequential translation steps; grey components depict the ribosome; colored rectangles represent tRNAs carrying amino acids shown as colored circles; the colored line along which ribosomes and tRNAs assemble represents mature mRNA with its nucleotide sequence), visualized in the bottom left (connected via a black arrow from right to left). It also promotes selenoprotein synthesis (indicated by a black arrow from top right to bottom left), shown in the bottom center. Selenoproteins contribute to the reduction (thick downward arrow) of reactive oxygen species (ROS, indicated by a black arrow), ultimately leading to decreased activation of the NF-κB signaling pathway. Created in BioRender (https://www.biorender.com/).

Figure 2

Family tree. The top white square and circle represent the consanguineous parents of the proband (father and mother, respectively). The bottom white circle and square represent healthy siblings of the proband (sister and brother, respectively), and the black square represents the described patient.

Figure 3

Craniofacial dysmorphism and brain imaging: (A,B) frontal, and side view of proband’s craniofacial dysmorphisms (i.e., coarse facial features, bitemporal narrowing, bilateral frontal and parietal bossing, high forehead, triangular face, synophrys, epicanthus, hypertelorism, bilateral ptosis, depressed nasal bridge, low-set overfolded dysmorphic ears with thick earlobes, long deep philtrum, thick lips, pointed chin). (C–E) A brain MRI was performed at the age of 3. (C) sagittal T1-weighted MRI image shows mild hypoplasia of posterior corpus callosum and mild inferior vermis hypoplasia with enlarged cisterna magna; (D) and (E) respectively, axial and coronal T2w MRI images showing lateral ventricles asymmetry with few dilated perivascular spaces (D) and left incomplete hippocampal inversion (E). (F) EEG shows poor organization with multifocal spike and wave discharges, prevalent in temporo-posterior regions.