ICNC Abstracts, ICNC 2018

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Developmental delay and cerebellar atrophy due to novel pathogenic variants in Gemin5 gene
Deepa Soundara Rajan

Last modified: 2018-09-09


Introduction: 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. There are no pathogenic variants in GEMIN5 identified to date in publicly available databases.
Methods: Whole-exome sequencing was used in children identified through the neurogenetic clinic with developmental delay and cerebellar atrophy, to identify novel autosomal recessive variants in GEMIN5 gene.  Functional characterization of the variants was pursued using drosophila knockouts.
Case Description/results: We identified novel homozygous variants in the GEMIN5 gene in three unrelated patient families. Clinical phenotype of affected children included developmental delay, central hypotonia and ataxia. MRI Brain showed cerebellar atrophy in all these patients. There were no obvious neurological symptoms among the heterozygous parents or siblings.  To examine the functional consequences of the homozygous variants in GEMIN5, we knocked down endogenous rigor mortis gene (fly homologue of human GEMIN5). Developmental delay, motor dysfunction and premature lethality were noted in the knockouts. Our preliminary observations suggest that these GEMIN5 variants are pathogenic.
Conclusion/Discussion: 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.

Future Directions: Functional analysis on IPSC's from patient cells that are currently being differentiated into neuronal cells in our lab.


GEMIN, cerebellar atrophy, developmental delay

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