Submission Details

DHDDS was first reported in relation to DHDDS-CDG (DHDDS-congenital disorder of glycosylation), an autosomal recessive disorder in 2011 (Züchner et al, PMID: 21295283; Zelinger et al, PMID: 21295282). DHDDS encodes the catalytic subunit of cis-prenyltransferase (cis-PTase). cis-PTase is a heterotetramer composed of two heterodimers of DHDDS (dehydrodolichyl diphosphate synthase) and the Nogo-B receptor (NgBR) that is required for the biosynthesis of dolichol, an essential lipid serving as glycosyl moiety carrier for protein N-glycosylation (Bar-El et al, 2019; PMID: 31661879; Bar-El et al, 2020; PMID: 33077723).

In OMIM, DHDDS is associated with 3 conditions:- “retinitis pigmentosa 59” (MIM#613861); “congenital disorder of glycosylation, type 1bb” (MIM# 613861); and “developmental delay and seizures with or without movement abnormalities” (MIM# 617836). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern for “retinitis pigmentosa 59” and “congenital disorder of glycosylation, type 1bb”. In fact, OMIM has given these two disorders the same MIM#, although note is made that the association of DHDDS with “congenital disorder of glycosylation, type 1bb” is described as provisional in OMIM. Due to the possibility for that additional symptoms could be present but mild in individuals reported with only retinal dystrophy and that additional symptoms may develop later in life, “retinitis pigmentosa 59” and “congenital disorder of glycosylation, type 1bb” were lumped together for the purposes of this curation as “DHDDS-CDG”. In contrast, “developmental delay and seizures with or without movement abnormalities” (MIM# 617836) typically results from de novo, heterozygous variants, and does not include retinal dystrophy as part of the phenotypic characteristics (Mehta and Lal, 2023, PMID: 36628425). Therefore, this condition will be curated separately.

Five variants (3 missense, one nonsense, one intronic) that have been reported in 12 probands in 7 publications are included in this curation (Züchner et al, 2011, PMID: 21295283; Sabry et al, 2016, PMID: 27343064; Biswas et al, 2017, PMID: 28130426; Kimchi et al, 2018, PMID: 29276052; Diñeiro et al, 2020, PMID: 32483926; Mousa et al, 2022, PMID: 36046393). To date, the majority of individuals reported in the literature with biallelic variants in DHDDS have been diagnosed with retinal dystrophy, typically described as retinitis pigmentosa, and are homozygous for a missense variant, p.Lys42Glu, that is a founder variant in the Ashkenazi Jewish population. At least 30 homozygotes have been reported in the literature, as well individuals who are compound heterozygous for p.Lys42Glu and another missense change (Wen et al, 2013, PMID: 24078709; Biswas et al, 2017, PMID: 28005406; Ramkumar et al, 2017, PMID: 28130426; Stone et al, 2017, PMID: 28559085Kimchi et al, 2018, PMID: 29276052; Sharon et al, 2020, PMID: 31456290). In addition to individuals reported with retinal dystrophy, without mention of other symptoms, two families have been described with a more complex phenotype that includes retinal dystrophy. In one of these families two affected siblings, homozygous for p.Lys42Glu, were reported with retinal dystrophy and later onset of neurological features including ataxia (Mousa et al, 2022, PMID: 36046393). In the other family, two children were severely affected from a young age with seizures, severe global developmental delay, no ERG response, and sensorineural deafness (Sabry et al, 2016, PMID: 27343064). In addition to individual case-level evidence, segregation data from two small families, each with 3 affected and one unaffected sibling (Züchner et al, 2011, PMID: 21295283; Zelinger et al, 2011, PMID: 21295282), and data from a single variant (p.Lys42Glu) case-control comparison between Ashkenazi Jewish individuals with and without retinal dystrophy (Zelinger et al, 2011, PMID: 21295282), supported this gene-disease relationship. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached.

This gene-disease relationship is also supported by experimental evidence including the biochemical function of the gene product, which is consistent with the finding of shortened dolichol chains in patients (Bar-El et al, 202, PMID: 33077723; Wen et al, 2013, PMID: 24078709), functional alteration resulting from siRNA knockdown in HepG2 cells (Sabry et al, 2016, PMID: 27343064), protein interaction between the gene products of DHDDS and NUS1, a gene that when altered has also been associated with congenital disorder of glycosylation (Harrison et al, 2011, PMID: 21572394), and the features reported in various animal models (see Fliesler et al, 2022, PMID: 36362109 for review), including a p.Lys42Glu knock-in mouse (see Fliesler et al, 2022, PMID: 36362109 for review), a rod-specific Dhdds knock-out mouse (Ramachandra et al, 2020, PMID: 32526701), and in zebrafish and Drosophila with Dhdds orthologs knocked down by siRNA (Züchner et al, 2011, PMID: 21295283; Brandwine et al 2021, PMID: 34290587). A review of all animal models for “retinitis pigmentosa 59” is available (Fliesler et al, 2022, PMID: 36362109).

In summary, DHDDS is definitively associated with autosomal recessive DHDDS-CDG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on April 6th, 2023 (SOP version 9).