Novel autosomal recessive variants in GEMIN5 gene lead to developmental delay motor dysfunction, and cerebellar atrophy. (P1.6-044)

Objective: Functional characterization of novel variants in GEMIN5 gene, identified in patients with developmental delay, motor dysfunction and cerebellar atrophy. Background: GEMIN5, an RNA-binding protein is essential for assembly of the SMN complex. It facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. It is also involved in regulating the splicing of pre-mRNAs and has been shown to bind snRNA-binding protein of the SMN complex. While it is well known that disruption of SMN proteins leads to Spinal Muscular Atrophy, no pathogenic variants in GEMIN5 have been identified in publicly available databases. Design/Methods: Whole-exome sequencing done on patients with hypotonia, developmental delay, gait abnormalities and cerebellar atrophy identified novel homozygous variants in GEMIN5 gene. Functional characterization of these variants was pursued. Results: Homozygous variants in the GEMIN5 gene were identified in patients with clinical phenotype of developmental delay, central hypotonia and ataxia. MRI Brain showed cerebellar atrophy in all affected individuals. No obvious neurological symptoms were noted in the heterozygous parents or siblings. To examine the functional consequences of these variants, RNAi-mediated knockdown of endogenous rigor mortis gene (fly homologue of human GEMIN5) caused developmental delay, motor dysfunction and premature lethality suggesting that loss-of-function of GEMIN5 is detrimental. Utilizing CRISPR/cas9, we introduced equivalent mutations in mice. Heterozygotes were noted to be asymptomatic similar to the our patient cohort and are currently being crossed to get homozygotes. Patient derived iPSC cell lines have been created and currently being differentiated into motor neurons to better understand the molecular pathways. Conclusions: Here we provide the first evidence that patients carrying autosomal recessive mutations in GEMIN5 display neurological symptoms. Our data suggests that pathogenic mutations in GEMIN5 perturb the physiological functions, as loss-of-function of GEMIN5 protein recapitulates clinical symptoms in flies. Disclosure: Dr. Rajan has nothing to disclose. Dr. Oliver has nothing to disclose. Dr. Grant has nothing to disclose. Dr. Pandey has nothing to disclose.