Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation

Marion Coolen*, Nami Altin, Karthyayani Rajamani, Eva Pereira, Karine Siquier-Pernet, Emilia Puig Lombardi, Nadjeda Moreno, Giulia Barcia, Marianne Yvert, Annie Laquerrière, Aurore Pouliet, Patrick Nitschké, Nathalie Boddaert, Antonio Rausell, Féréchté Razavi, Alexandra Afenjar, Thierry Billette de Villemeur, Almundher Al-Maawali, Khalid Al-Thihli, Julia BaptistaAna Beleza-Meireles, Catherine Garel, Marine Legendre, Antoinette Gelot, Lydie Burglen, Sébastien Moutton, Vincent Cantagrel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Original languageEnglish
Pages (from-to)909-927
Number of pages19
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - May 5 2022


  • PRDM13
  • Purkinje cells
  • brainstem
  • cerebellum
  • inferior olive nuclei
  • neurodevelopment
  • neuronal specification
  • olivopontocerebellar hypoplasia
  • zebrafish

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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