DPH5 is located on chromosome 1 at 1p21.2 and encodes the protein diphthamide biosynthesis 5, an essential component in catalyzing the second step of diphthamide moiety formation on eukaryotic elongation factor 2 (EEF2).
DPH5 was first reported in relation to an autosomal recessive developmental disorder, termed DPH5-related diphthamide-deficiency syndrome in 2022 (Shankar et al., 2022 PMID: 35482014). The individuals described in this paper had homozygous or compound heterozygous pathogenic variants in the DPH5 gene. Their clinical features included craniofacial dysmorphism (broad forehead, frontal bossing, sparse eyebrows, epicanthal folds, broad nasal bridge, triangular chin), short stature, intellectual disability, feeding difficulties, global developmental delay, absence of speech, and delayed ability to walk.
Four variants (missense, frameshift, nonsense) reported in three probands in one publication (PMID: 35482014) are included in this curation. Within this cohort, two families also reported a history of miscarriages and early infant deaths with variable involvement of cardiac and respiratory systems.
This gene-disease relationship is supported by experimental evidence such as in vitro functional assays (PMID: 3346227), and studies involving cell cultures and non-human model organisms (PMIDs: 28245596, 1508200, 18460012, 35482014). The mechanism of disease is hypothesized to be loss-of-function, whereby pathogenic variants cause a marked decrease in the abundance of the modified histidine residue, known as diphthamide, on EEF2. The absence of this modification impairs the function of EEF2 in maintaining translational fidelity, potentially engendering spurious frameshift events (PMIDs: 23468660, 37246715).
In summary, there is limited evidence to support the relationship between DPH5 and autosomal recessive DPH5-related diphthamide-deficiency syndrome. Although more evidence is needed to support a causal role, no convincing evidence has been reported that contradicts this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting dated October 24, 2024 (SOP Version 11).
DPH5 is located on chromosome 1 at 1p21.2 and encodes the protein diphthamide biosynthesis 5, an essential component in catalyzing the second step of diphthamide moiety formation on eukaryotic elongation factor 2 (EEF2).
DPH5 was first reported in relation to an autosomal recessive developmental disorder, termed DPH5-related diphthamide-deficiency syndrome in 2022 (Shankar et al., 2022 PMID: 35482014). The individuals described in this paper had homozygous or compound heterozygous pathogenic variants in the DPH5 gene. Their clinical features included craniofacial dysmorphism (broad forehead, frontal bossing, sparse eyebrows, epicanthal folds, broad nasal bridge, triangular chin), short stature, intellectual disability, feeding difficulties, global developmental delay, absence of speech, and delayed ability to walk.
Four variants (missense, frameshift, nonsense) reported in five probands in one publication (PMID: 35482014) are included in this curation. Within this cohort, two families also reported a history of miscarriages and early infant deaths with variable involvement of cardiac and respiratory systems.
This gene-disease relationship is supported by experimental evidence such as in vitro functional assays (PMID: 3346227), and studies involving cell cultures and non-human model organisms (PMIDs: 28245596, 1508200, 18460012, 35482014). The mechanism of disease is hypothesized to be loss-of-function, whereby pathogenic variants cause a marked decrease in the abundance of the modified histidine residue, known as diphthamide, on EEF2. The absence of this modification impairs the function of EEF2 in maintaining translational fidelity, potentially engendering spurious frameshift events (PMIDs: 23468660, 37246715).
In summary, there is limited evidence to support the relationship between DPH5 and autosomal recessive DPH5-related diphthamide-deficiency syndrome. Although more evidence is needed to support a causal role, no convincing evidence has been reported that contradicts this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting dated October 24, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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