Expanding the Phenotypic Spectrum Associated with DPH5-Related Diphthamide Deficiency

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.

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.

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.

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.