LSM7 variants involving key amino-acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy

Matis Crespin; Karine Siquier-Pernet; Pauline Marzin; Christine Bole-Feysot; Valérie Malan; Patrick Nitschké; Marie Hully; Charles-Joris Roux; Michel Lemoine; Marlène Rio; Nathalie Boddaert; Thomas Courtin; Vincent Cantagrel

doi:10.1016/j.xhgg.2024.100372

LSM7 variants involving key amino-acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy

HGG Adv. 2024 Oct 16:100372. doi: 10.1016/j.xhgg.2024.100372. Online ahead of print.

Authors

Affiliations

¹ AP-HP, Necker Enfants-Malades hospital, Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, Paris, F-75015, France.
² Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory,75015, Paris, France.
³ Université Paris Cité, Genomics Platform, Imagine Institute, INSERM UMR 1163, 75015, Paris, France.
⁴ AP-HP, Necker Enfants-Malades hospital, Fédération de Génétique et Médecine Génomique, Service de Médecine Génomique des Maladies Rares, Paris, F-75015, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory,75015, Paris, France.
⁵ Université Paris Cité, Bioinformatics Core Facility, Imagine Institute, INSERM UMR 1163, 75015, Paris, France.
⁶ Département de Neurologie Pédiatrique, Necker Enfants-Malades hospital, APHP Centre, Université Paris Cité, 75015, Paris, France; AP-HP, Necker Enfant Malade hospital, Unité de médecine physique et de réadaptation, Paris, F-75015, France.
⁷ Département de Radiologie Pédiatrique, INSERM UMR 1163 and INSERM U1299, Institut Imagine, AP-HP, Necker Enfant Malade hospital, 75015, Paris, France.
⁸ AP-HP, Necker Enfant Malade hospital, Unité de médecine physique et de réadaptation, Paris, F-75015, France.
⁹ Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory,75015, Paris, France. Electronic address: [email protected].

PMID: 39420558
DOI: 10.1016/j.xhgg.2024.100372

Abstract

Cerebellar atrophy and hypoplasia are usually identified on MRI performed on children presenting signs of cerebellar ataxias, developmental delay and intellectual disability. These signs can be associated with hypo- or de-myelinating leukodystrophies. A recent study reported two cases: one child diagnosed with leukodystrophy and cerebellar atrophy, harboring a homozygous variant in LSM7 and another one who died in utero, presumed to have another homozygous variant in LSM7, based on parents' genotype. LSM7 encodes a subunit of the LSM complex, involved in pre-RNA maturation and mRNA degradation. Consequently, it has been suggested as a strong candidate disease gene. This hypothesis was supported by functional investigations of the variants. Presently, we report a patient with neurodevelopmental defects, leukodystrophy and cerebellar atrophy, harboring compound heterozygous missense variants in the LSM7 gene. One of these variants is the same as the one carried by the first case previously reported. The other one is at the same position as the variant potentially carried by the second case previously reported. Based on comparable neuroimaging, clinical features and the involvement of the same amino-acids previously demonstrated as key for LSM complex function, we confirm that LSM7 disruption causes a neurodevelopmental disorder characterized by leukodystrophy and cerebellar atrophy.