2. Academic Validation
  3. Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

  • Hum Mol Genet. 2020 Aug 3;29(13):2218-2239. doi: 10.1093/hmg/ddaa108.
Anne Slavotinek 1,  Doriana Misceo 2,  Stephanie Htun 1,  Linda Mathisen 2,  Eirik Frengen 2,  Michelle Foreman 3,  Jennifer E Hurtig 3,  Liz Enyenihi 4,  Maria C Sterrett 4,  Sara W Leung 4,  Dina Schneidman-Duhovny 5,  Juvianee Estrada-Veras 6,  Jacque L Duncan 7,  Charlotte A Haaxma 8,  Erik-Jan Kamsteeg 9,  Vivian Xia 1,  Daniah Beleford 1,  Yue Si 10,  Ganka Douglas 10,  Hans Einar Treidene 11,  Ambro van Hoof 3,  Milo B Fasken 4,  Anita H Corbett 4
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
  • 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo 0450, Norway.
  • 3 Department of Microbiology and Molecular Genetics, University of Texas Health Science Center-Houston, Houston, TX 77030, USA.
  • 4 Department of Biology, Emory University, Atlanta, GA 30322, USA.
  • 5 School of Computer Science and Engineering and the Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • 6 Department of Pediatrics-Medical Genetics and Metabolism, Uniformed Services University/Walter Reed NMMC Bethesda, MD 20889, USA.
  • 7 Department of Ophthalmology, University of California, San Francisco, CA 94143, USA.
  • 8 Department of Pediatric Neurology, Amalia Children's Hospital and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
  • 9 Department of Human Genetics, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
  • 10 GeneDx Inc., MD 20877, USA.
  • 11 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo 0450, Norway.
PMID: 32504085 DOI: 10.1093/hmg/ddaa108
Abstract

The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

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