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Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form
  1. Weiyi Mu1,
  2. Teresa Heller2 and
  3. Kristin W Barañano3
  1. 1Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
  2. 2Department of Biology, University of Virginia, Charlottesville, Virginia, USA
  3. 3Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Kristin W Barañano; kwb{at}jhmi.edu

Abstract

Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype–phenotype associations.

  • neuro genetics
  • movement disorders (other than Parkinsons)
  • brain stem / cerebellum

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Footnotes

  • Contributors WM, TH and KWB contributed to the conception of this work; the acquisition, analysis and interpretation of data; the drafting of this manuscript; approved the final version of this manuscript and agreed to be held accountable for all aspects of this work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer-reviewed.

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