Expanding the Phenotypic Spectrum Associated with DPH5-Related Diphthamide Deficiency

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Medicine

Background:

• Neurodevelopmental disorders (NDDs) are diverse conditions impacting brain development, often stemming from genetic mutations.
• Ribosomopathies, a subset of NDDs, arise from defects in ribosomal function, including diphthamide synthesis.
• Loss-of-function mutations in diphthamide biosynthesis genes like DPH5 cause developmental delay, intellectual disability, and multisystemic issues.

Purpose of the Study:

• To investigate the genetic basis and clinical presentation of DPH5-related diphthamide deficiency syndrome.
• To explore genotype-phenotype correlations in patients with DPH5 mutations.

Main Methods:

• Multidisciplinary clinical, neurological, and dysmorphological evaluations.
• Brain MRI and craniofacial assessment using GestaltMatcher.
• Whole exome sequencing (WES) with trio-based analysis and bioinformatic variant assessment.

Main Results:

• The affected subject presented a previously reported missense variant (p.His260Arg) in DPH5.
• This variant exhibited hypomorphic behavior, leading to a milder phenotype compared to previously described cases.
• Genotype-phenotype correlations were suggested by the observed variant and clinical presentation.

Conclusions:

• The specific DPH5 variant likely contributes to a milder form of diphthamide deficiency syndrome.
• Clinical features including short stature, relative macrocephaly, heart defects, and craniofacial anomalies warrant consideration of Noonan syndrome in differential diagnosis.