Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Adolescent Adult Aged Animals Calcinosis / complications Child Child, Preschool Consanguinity Disease Models, Animal Female Genetic Association Studies Heterozygote Humans Infant Infant, Newborn Leukoencephalopathies / complications Male Middle Aged Pathology, Molecular RNA, Small Nucleolar / genetics Young Adult Zebrafish / genetics

C/D box snoRNA U8 Labrune syndrome SNORD118 coats plus leukoencephalopathy with calcifications and cysts ribosomopathy

Journal

American journal of medical genetics. Part A

ISSN: 1552-4833

Titre abrégé: Am J Med Genet A

Pays: United States

ID NLM: 101235741

Informations de publication

Date de publication:
01 2021

Historique:

received: 15 07 2020

revised: 03 09 2020

accepted: 16 09 2020

pubmed: 9 10 2020

medline: 30 6 2021

entrez: 8 10 2020

Statut: ppublish

Résumé

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Identifiants

DOI: 10.1002/ajmg.a.61907 PMID: 33029936

pubmed: 33029936

doi: 10.1002/ajmg.a.61907

doi:

Substances chimiques

RNA, Small Nucleolar 0

SNORD118 RNA, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

15-25

Informations de copyright

Références

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