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Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum
Author(s) -
Crow Yanick J,
Marshall Heather,
Rice Gillian I,
Seabra Luis,
Jenkinson Emma M,
Baranano Kristin,
Battini Roberta,
Berger Andrea,
Blair Edward,
Blauwblomme Thomas,
Bolduc Francois,
Boddaert Natalie,
Buckard Johannes,
Burnett Heather,
Calvert Sophie,
Caumes Roseline,
Ng Andy CheukHim,
Chiang Diana,
Clifford David B,
Cordelli Duccio M,
Burca Anna,
Demic Natasha,
Desguerre Isabelle,
De Waele Liesbeth,
Di Fonzo Alessio,
Dunham S. Richard,
Dyack Sarah,
Elmslie Frances,
Ferrand Mickaël,
Fisher Gemma,
Karimiani Ehsan Ghayoor,
Ghoumid Jamal,
Gibbon Frances,
Goel Himanshu,
Hilmarsen Hilde T,
Hughes Imelda,
Jacob Anu,
Jones Elizabeth A,
Kumar Ram,
Leventer Richard J,
MacDonald Shelley,
Maroofian Reza,
Mehta Sarju G,
Metz Imke,
Monfrini Edoardo,
Neumann Daniela,
Noetzel Michael,
O'Driscoll Mary,
Õunap Katrin,
Panzer Axel,
Parikh Sumit,
Prabhakar Prab,
Ramond Francis,
Sandford Richard,
Saneto Russell,
Soh Calvin,
Stutterd Chloe A,
Subramanian Gopinath M,
Talbot Kevin,
Thomas Rhys H,
Toro Camilo,
Touraine Renaud,
Wakeling Emma,
Wassmer Evangeline,
Whitney Andrea,
Livingston John H,
O'Keefe Raymond T,
Badrock Andrew P
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61907
Subject(s) - proband , phenotype , genetics , biology , leukoencephalopathy , compound heterozygosity , genotype , allele , mutation , gene , disease , medicine , pathology
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.