Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum

Yanick J. Crow, Heather Marshall, Gillian I. Rice, Luis Seabra, Emma M. Jenkinson, Kristin Baranano, Roberta Battini, Andrea Berger, Edward Blair, Thomas Blauwblomme, Francois Bolduc, Natalie Boddaert, Johannes Buckard, Heather Burnett, Sophie Calvert, Roseline Caumes, Andy Cheuk Him Ng, Diana Chiang, David B. Clifford, Duccio M. CordelliAnna de Burca, Natasha Demic, Isabelle Desguerre, Liesbeth De Waele, Alessio Di Fonzo, S. Richard Dunham, Sarah Dyack, Frances Elmslie, Mickaël Ferrand, Gemma Fisher, Ehsan Ghayoor Karimiani, Jamal Ghoumid, Frances Gibbon, Himanshu Goel, Hilde T. Hilmarsen, Imelda Hughes, Anu Jacob, Elizabeth A. Jones, Ram Kumar, Richard J. Leventer, Shelley MacDonald, Reza Maroofian, Sarju G. Mehta, Imke Metz, Edoardo Monfrini, Daniela Neumann, Michael Noetzel, Mary O'Driscoll, Katrin Õunap, Axel Panzer, Sumit Parikh, Prab Prabhakar, Francis Ramond, Richard Sandford, Russell Saneto, Calvin Soh, Chloe A. Stutterd, Gopinath M. Subramanian, Kevin Talbot, Rhys H. Thomas, Camilo Toro, Renaud Touraine, Emma Wakeling, Evangeline Wassmer, Andrea Whitney, John H. Livingston, Raymond T. O'Keefe, Andrew P. Badrock

Résultat de recherche: Articleexamen par les pairs

21 Citations (Scopus)

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.

Langue d'origineEnglish
Pages (de-à)15-25
Nombre de pages11
JournalAmerican Journal of Medical Genetics, Part A
Volume185
Numéro de publication1
DOI
Statut de publicationPublished - janv. 2021

Note bibliographique

Funding Information:
We sincerely thank all the patients, their families and collaborating physicians who provided help in compiling the information included in this manuscript. The study was supported by a grant to Y. J. C. and R. T. O'K. from the Great Ormond Street Hospital Charity (V4017). Y. J. C. also acknowledges a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” program bearing the reference ANR‐10‐IAHU‐01 and the MSDAvenir fund (DEVO‐DECODE Project). The University of Cambridge has received salary support in respect of R.S. from the NHS in the East of England through the Clinical Academic Reserve. In this regard, the views expressed are those of the authors and not necessarily those of the NHS or Department of Health. K.Õ. is supported by an Estonian Research Council grant (PRG471).

Funding Information:
We sincerely thank all the patients, their families and collaborating physicians who provided help in compiling the information included in this manuscript. The study was supported by a grant to Y. J. C. and R. T. O'K. from the Great Ormond Street Hospital Charity (V4017). Y. J. C. also acknowledges a state subsidy managed by the National Research Agency (France) under the ?Investments for the Future? program bearing the reference ANR-10-IAHU-01 and the MSDAvenir fund (DEVO-DECODE Project). The University of Cambridge has received salary support in respect of R.S. from the NHS in the East of England through the Clinical Academic Reserve. In this regard, the views expressed are those of the authors and not necessarily those of the NHS or Department of Health. K.?. is supported by an Estonian Research Council grant (PRG471).

Publisher Copyright:
© 2020 Wiley Periodicals LLC

ASJC Scopus Subject Areas

  • Genetics
  • Genetics(clinical)

PubMed: MeSH publication types

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

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