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Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease

Gardner, E; Bailey, M; Schulz, A; Aristorena, M; Miller, N; Mole, SE; (2019) Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease. Human Mutation , 40 (11) pp. 1924-1938. 10.1002/humu.23860. Green open access

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Abstract

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive condition caused by variants in the TPP1 gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase I (TPP1). We update on the spectrum of TPP1 variants associated with CLN2 disease, comprising 131 unique variants from 389 individuals (717 alleles) collected from literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1G>C and c.622C>T (p.(Arg208*)), collectively occur in 60% of affected individuals in the sample, and account for 50% of disease-associated alleles. At least 86 variants (66%) are private to single families. Homozygosity occurs in 45% of individuals where both alleles are known (87% of reported individuals). Atypical CLN2 disease, TPP1 enzyme deficiency with disease onset and/or progression distinct from classic late-infantile CLN2, represents 13% of individuals recorded with associated phenotype. NCBI ClinVar currently holds records for 37% of variants collected here. Effective CLN2 disease management requires early diagnosis; however, irreversible neurodegeneration occurs before diagnosis is typically reached at age 5. Timely classification and public reporting of TPP1 variants is essential as molecular testing increases in use as a first-line diagnostic test for pediatric-onset neurological disease. This article is protected by copyright. All rights reserved.

Type: Article
Title: Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/humu.23860
Publisher version: https://doi.org/10.1002/humu.23860
Language: English
Additional information: © 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: genotype-phenotype correlation, late-infantile neuronal ceroid lipofuscinosis, lysosomal storage disorders, neurodegeneration, tripeptidyl peptidase I
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science
URI: https://discovery.ucl.ac.uk/id/eprint/10078050
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