Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease
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Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease. / Gardner, Emily; Bailey, Mitch; Schulz, Angela; Aristorena, Mikel; Miller, Nicole; Mole, Sara E.
in: HUM MUTAT, Jahrgang 40, Nr. 11, 11.2019, S. 1924-1938.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease
AU - Gardner, Emily
AU - Bailey, Mitch
AU - Schulz, Angela
AU - Aristorena, Mikel
AU - Miller, Nicole
AU - Mole, Sara E
N1 - © 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.
PY - 2019/11
Y1 - 2019/11
N2 - 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 the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1 G>C and c.622 C>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 a 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.
AB - 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 the literature review, public databases, and laboratory communications. Previously unrecorded individuals were added to the UCL TPP1-specific database. Two known pathogenic variants, c.509-1 G>C and c.622 C>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 a 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.
KW - Alleles
KW - Aminopeptidases/chemistry
KW - Animals
KW - Biomarkers
KW - Databases, Genetic
KW - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry
KW - Disease Models, Animal
KW - Genetic Association Studies
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Humans
KW - Molecular Dynamics Simulation
KW - Mutation
KW - Neuronal Ceroid-Lipofuscinoses/diagnosis
KW - Phenotype
KW - Protein Conformation
KW - Serine Proteases/chemistry
KW - Structure-Activity Relationship
U2 - 10.1002/humu.23860
DO - 10.1002/humu.23860
M3 - SCORING: Journal article
C2 - 31283065
VL - 40
SP - 1924
EP - 1938
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 11
ER -