IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia

Solveig Heide, Claire-Sophie Davoine, Paulina Cunha, Clarisse Scherer-Gagou, Boris Keren, Giovanni Stevanin, Perrine Charles, Delphine Heron, Alexis Brice, Alexandra Durr
Neurology Genetics. 2023-12-01; 9(6):
DOI: 10.1212/nxg.0000000000200096

1. Neurol Genet. 2023 Oct 19;9(6):e200096. doi: 10.1212/NXG.0000000000200096.
eCollection 2023 Dec.

IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia.

Heide S(1), Davoine CS(1), Cunha P(1), Scherer-Gagou C(1), Keren B(1), Stevanin
G(1), Charles P(1), Heron D(1), Brice A(1), Durr A(1).

Author information:
(1)From the Genetic Department (S.H., B.K., P. Charles, D.H., A.D.), Assistance
Publique-Hôpitaux de Paris (AP-HP) Pitié-Salpêtrière; Reference Center for Rare
Diseases « Intellectual disabilites of rare causes » « Déficiences
Intellectuelles de Causes Rares » (S.H., P. Charles, D.H.), Pitié-Salpêtrière
Hospital; Sorbonne Université (C.-S.D., P. Cunha, G.S., A.B., A.D.), Paris Brain
Institute (ICM Institut du Cerveau), INSERM, CNRS, Assistance Publique-Hôpitaux
de Paris (AP-HP); Department of Neurology (C.S.-G.), University Hospital
d’Angers; and INCIA (G.S.), EPHE, Université de Bordeaux, France.

BACKGROUND AND OBJECTIVES: Neurodevelopmental and neurodegenerative disorders
have long been considered as different clinical and molecular entities, and only
a few genes are known to be involved in both processes. The IRF2BPL (interferon
regulatory factor 2 binding protein like) gene was implicated in a severe
pediatric phenotype characterized by developmental and epileptic encephalopathy
and early regression. In parallel, inherited IRF2BPL variants have been reported
in cohorts of patients with late-onset progressive dystonic and ataxic syndrome
with few information about the neurodevelopment of these patients. This study
aimed to describe both neurodevelopmental and neurodegenerative aspects of the
phenotype in adults with IRF2BPL pathogenic variant.
METHODS: We report here the clinical and molecular data of 18 individuals
carrying truncating IRF2BPL variants (identified by either exome or genome
sequencing), including a large pedigree of 16 patients presenting with a
neurodevelopmental disorder (NDD) associated with late-onset cerebellar ataxia
and atrophy.
RESULTS: Genome sequencing identified the p.(Gln117*) variant in a large family
first assessed for familial ataxia, with multiple individuals presenting with
NDD. The p.(Ser313*) variant was identified by exome sequencing in a second
family with a young adult patient with NDD without ataxia which was inherited
from her asymptomatic mother, suggesting incomplete penetrance of IRF2BPL-linked
disorders.
DISCUSSION: This study illustrates the importance of neurologic evaluation of
adult patients initially diagnosed with NDD to detect a late-onset
neurodegenerative condition. Two different disorders may be clinically diagnosed
in the same family, when not considering that NDD and late cerebellar changes
may be part of the same molecular spectrum such as for IRF2BPL.