Submission Details

DPH1 is located on chromosome 17 at 17p13.3 and encodes for diphthamide biosynthesis 1, one of the essential components of the enzyme catalyzing the first step of diphthamide formation on eukaryotic elongation factor 2 (EEF2). DPH1 was first reported in relation to autosomal recessive developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (DEDSSH1) in 2015 (Loucks et al., 2015 PMID: 26220823). DEDSSH1 is caused by homozygous or compound heterozygous pathogenic variants in the DPH1 gene. The clinical profile of this disease includes craniofacial dysmorphism (an abnormal skull shape, hypertelorism, downslanting palpebral fissures, epicanthal folds, low-set ears, depressed nasal bridge, micrognathia), short stature, ectodermal anomalies (such as sparse eyebrows, eyelashes, and scalp hair, hypoplastic toenails), developmental delay, and intellectual disability. Some patients have cerebral/cerebellar malformations and mild renal involvement. Nine unique variants (six missense, three frameshift) reported in fourteen probands in seven publications (PMID: 26220823, 29362492, 29410513, 30877278,33704902, 34645488,32732226) are included in this curation. The mechanism of disease is loss-of-function whereby pathogenic variants reduce the presence of diphthamide on eEF2, and therefore reduced DPH1 functionality. A total of 11 genetic evidence points was reached, considering case-level data. This gene-disease relationship is also supported by a mouse model, protein interaction, and biochemical data (PMID: 24895408, 15485916). In summary, there is definitive evidence supporting the relationship between DPH1 and autosomal recessive developmental delay with short stature, dysmorphic facial features, and sparse hair 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 15th, 2024 (SOP Version 10)