Submission Details

The GTPBP2 (guanosine triphosphate binding protein 2) gene is located on chromosome 6 at 6p21 and encodes a member of the GTP-binding superfamily. This gene was first reported in connection with Jaberi-Elahi syndrome (JABELS) in 2016 (Jaberi et a., PMID: 26675814). This disorder is characterized by developmental, neurological (epilepsy, contractures and/or hypotonia), craniofacial (microcephaly and/or facial dysmorphism), skeletal (scoliosis or kyphoscoliosis), ectodermal (thin, sparse hair, eyebrows and/or abnormal dentition), and ocular features (retinal degeneration, cataract, and/or visual impairment). More recently, this condition has also been described as Gtpbp1/2-related ectodermal neurodevelopmental (GREND) syndrome) (Salpietro et al., 2024, PMID:38118446). Disease severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, while others do not achieve any motor control, are non-ambulatory and nonverbal. Only the first reported family was found to have iron accumulation in the brain, but these individuals were clinically examined later in adulthood, while more recent reports were examined in childhood. It is possible that the iron accumulation brain phenotype is a later onset manifestation of disease. The mode of inheritance is autosomal recessive; all but two of the reported affected families to date have been consanguineous.

The mechanism of disease appears to be loss of function, as most variants identified are truncations, frameshifts, or splice variants, though 5 missense variants have also been reported. At least eight unique variants (5 nonsense, 2 splice-site, 1 missense) that have been reported in eight probands from five publications (PMIDs: 26675814, 28454995, 29449720, 30790272, 38852771) are included in this curation. 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 a mouse model with a splice donor variant in intron 6 of gtpbp2 which recapitulates the cerebellar, retinal, and gait abnormalities found in humans (Ishimura et al., 2014, PMID: 25061210). Crossing mice with this variant to a different strain with gtpbp2 intact rescues the disease phenotypes. In addition, expression studies of human postmortem brain tissue show that GTPBP2 is highly expressed in the brain regions disrupted in JABELS/GRENDS patients (Salpietro et al., 2024, PMID: 38118446).

In summary, there is definitive evidence supporting the relationship between GTPBP2 and autosomal recessive JABELS/GREND syndrome. 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 Syndromic Disorders GCEP on the meeting date August 16th, 2024 (SOP Version 10).