GORAB was first reported in relation to geroderma osteodysplastica (GO), in 2008 (Hennies et al, PMID: 18997784). GO is an autosomal recessive segmental progeroid disorder that affects the skin, connective tissues, and bone. It is characterized by wrinkled skin, joint laxity, a prematurely aged facial appearance, severe osteoporosis leading to frequent fractures, malar and mandibular hypoplasia, variable growth retardation, and mild intellectual disability in some cases. GO is the only condition known to result from variants in GORAB.
Twelve variants (7 nonsense, 3 frameshift, 2 missense) that have been reported in ten probands in four publications (Hennies et al, 2008 PMID: 18997784; Al-Dosari & Alkuraya, 2009, PMID: 19681135; Takeda et al, PMID: 28807865, 2017; Saad et al, 2024, PMID: 39619733) are included in this curation. Segregation evidence from Mennonite families was also included. A founder variant, c.367G>T (p.Glu123Ter), has been identified in that population (Hennies et al, 2008 PMID: 18997784). More evidence is available in the literature, but the maximum score for genetic evidence (>12 points) has been reached. The mechanism of pathogenicity is loss of function.
This gene-disease relationship is also supported by experimental evidence including biochemical function and mouse models (total 2 points). GORAB encodes a protein that localizes to the trans Golgi where it interacts with RAB6, regulates the level of active TGF-β, and stabilizes the COPI complex. It has been shown to be important in COPI-mediated retrograde trafficking of transGolgi enzymes, including glycosyltransferases. Loss of GORAB function leads to defective protein glycosylation and disorganization of the extracellular matrix, consistent with the clinical phenotype. Null mouse models die early in life and do not have a skin phenotype. Mouse models with conditional loss of Gorab in osteoblasts recapitulate the bone phenotype in human, with osteoporosis and multiple long bone fractures (Yang et al, 2017, PMID: 29108851; Chan et al, 2018, PMID: 29561836; Chan et al, 2024, 39234801).
In summary, there is definitive evidence supporting the relationship between GORAB and geroderma osteodysplastica, and autosomal recessive segmental progeroid condition. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on July 3, 2025 (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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