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Cited by 16Genetics and Neurodevelopmental DisordersFetal and Pediatric Neurological DisordersGenomics and Rare Diseases

Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement

Le Duc, Diana, Horn, Susanne, Jamra, Rami Abou, Schaper, Jörg, Wieczorek, Dagmar, Redler, Silke·2020·European Journal of Medical Genetics
DOI 10.1016/j.ejmg.2019.04.006
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Abstract

EXOSC3-related autosomal recessive neurodevelopmental disorders are rare entities with variable clinical course and prognosis. They are characterized by hypoplasia of cerebellar structures and pons, degeneration of the anterior horn cells and motor as well as neurocognitive impairment. Phenotypic expression is variable with an overall poor outcome. Current research suggests clear genotype-phenotype correlations among EXOSC3-pathogenic-variants carriers. Homozygosity for the EXOSC3 variant c.395A > C, p.(Asp132Ala) is proposed to lead to a rather mild phenotype compared to compound-heterozygous EXOSC3-pathogenic-variants carriers with lethal neurological disease in very early childhood. In this study, we report two siblings (21- and 8-year-old) affected by PCH1B with an unusual presentation. We identified compound heterozygosity for the well-established EXOSC3 variant c.395A > C, p.(Asp132Ala) and the novel variant c.572G > A, p.(Gly191Asp), expanding the genetic spectrum. Phenotypic presentation of the siblings was strikingly different from that of literature reports with a surprisingly mild disease manifestation and an unexpected intrafamilial variability. This study demonstrates the extensive clinical heterogeneity and the broad phenotypic spectrum associated with EXOSC3-associated disorders. Enlargement of sample sizes and reports of novel cases will be essential for the delineation of associated phenotypes.

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  • PCH1B patients who are carriers of compound heterozygous EXOSC3 D132A/G191D variants present with milder disease, without involving the pons, and show intrafamilial variability.

    “PCH1B patients who are carriers of compound heterozygous EXOSC3 D132A/G191D variants present with milder disease, without involving the pons, and show intrafamilial variability23,53,54.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [54]

  • The lesser thermodynamic severity of the G191C variant compared to G191D correlates well with less severe clinical outcomes observed in G191C homozygous patients compared to G191D homozygous patients.

    “Notably, the lesser thermodynamic severity of the G191C variant compared to G191D correlates well with less severe clinical outcomes observed in G191C homozygous patients (previously classified with complicated hereditary spastic paraplegia) compared to G191D homozygous patients (classified with moderate PCH1b) 23,53,54.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [54]

  • These findings could potentially explain the observation of intrafamily variability of EXOSC3 G191 variant associated disease severity.

    “These findings could potentially explain the observation of intrafamily variability of EXOSC3 G191 variant associated disease severity54.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [54]

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Authors
Le Duc, D., Horn, S., Jamra, R. A., Schaper, J., Wieczorek, D., & Redler, S.
Affiliations
  • Leipzig University (DE)
  • Heinrich Heine University Düsseldorf (DE)
Corresponding author
Redler, Silke
ORCID
Venue
European Journal of Medical Genetics
Publisher
Elsevier BV
Published
2020-02
Volume
63
Issue
2
Pages
103649
ISSN
1769-7212 (ISSN-L)
DOI
10.1016/j.ejmg.2019.04.006
OpenAlex
W2937366904
Cited by
16
References
15
Citations by year
2026: 4 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3
FWCI
1.35
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • European Journal of Medical Genetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
EXOSC3, autosomal recessive neurodevelopmental disorder, compound heterozygosity, novel pathogenic variant, cerebellar hypoplasia, anterior horn cell degeneration, genotype-phenotype correlation, intrafamilial variability, clinical heterogeneity, phenotypic spectrum
MeSH terms
Cerebellar Diseases, Cerebellum, Child, Female, Heterozygote, Homozygote, Humans, Male, Mutation, Phenotype, RNA-Binding Proteins, Siblings, Young Adult, Genetic Association Studies, Exosome Multienzyme Ribonuclease Complex

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