Submission Details

The GEMIN5 gene is located on chromosome 5 at 5q33.2 and encodes for a predominantly cytoplasmic protein that is a component of the survival of motor neurons (SMN) complex which is involved in the assembly and biogenesis of small nuclear ribonucleoproteins (snRNPs), the building blocks of the splicing machinery (PMIDs: 16857593, 18984161 and 20513430). Outside of the spliceosome, GEMIN5 has other functional roles including as a regulator of translation, ribosome-interacting protein, reprogramming factor in hair cells, signal recognition particle-interacting protein, and trans-splicing factor (PMIDs: 19066202, 25911097, 29771365, 32218991 and 23221635). GEMIN5 is expressed ubiquitously at the RNA and protein level (PMID: 28940711).

Biallelic variants in GEMIN5 were first reported in 2021 in association with a neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM), in 30 affected individuals from 22 unrelated families (Kour et al., PMID: 33963192). Phenotypic features include motor-predominant developmental delay, diagnosed within 2 years of life, and cerebellar atrophy on brain MRI. Most patients had non-progressive cognitive and speech delays, while some patients had central hypotonia, with variable muscle tone, deep tendon reflexes, and walking ability. The clinical course was mostly static, though some experienced progression. NEDCAM has been stratified into three subgroups, based on age of onset and severity (Rajan et al., 2022, PMID:35295849). In total, 11 biallelic variants (3 LOF, and 7 non-recurrent and 1 recurrent missense) from 7 unrelated families with 9 affected individuals with spastic ataxia and cerebellar atrophy were included in this curation. Additional variants have also been reported from various case studies, some of which include rarer congenital hypothyroidism and infantile spasm phenotypes; further highlighting the wide clinical spectrum and variable severity of NEDCAM (PMIDs: 34569062, 37479787 and 36980979).

The proposed mechanism of disease is biallelic loss of function. This gene-disease relationship is also supported by experimental evidence including expression and non-human model organisms (Drosophila, zebrafish). On the variant level, GEMIN5 variants in patient-derived iPSC neurons and lymphoblastoid cell lines show a reduction in protein expression, which in turns led to reduced protein and SMN complex interactions, ribosome dissociation and translation dysregulation (PMIDs: 35393353 and 34569062). On the gene level, the loss of GEMIN5 has been studied in Drosophila and Zebrafish homologues, which recapitulated the developmental delay and motor dysfunction, and dysplastic cerebellum observed in NEDCAM respectively (PMIDs: 33963192 and 34569062). In summary, there is definitive evidence supporting the relationship between GEMIN5 and NEDCAM. 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 Syndromic Disorders GCEP on September 6, 2023 (SOP Version 9).