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Observational Study
. 2021 Nov;44(6):1453-1462.
doi: 10.1002/jimd.12429. Epub 2021 Sep 7.

A diagnostic confidence scheme for CLN3 disease

Margaux C Masten  1 , Camille Corre  1 , Alex R Paciorkowski  1 , Amy Vierhile  1 , Heather R Adams  1 , Jennifer Vermilion  1 , Grace A Zimmerman  1 , Erika F Augustine  1   2 , Jonathan W Mink  1
Affiliations
Observational Study

A diagnostic confidence scheme for CLN3 disease

Margaux C Masten et al. J Inherit Metab Dis. 2021 Nov.

Abstract

Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Keywords: Batten disease; diagnosis; lysosomal disorders; natural history; neurodegenerative disease; neuronal ceroid lipofuscinosis.

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Figures

FIGURE 1
FIGURE 1
Diagnostic confidence flow chart (* Diagnostic evidence includes disease-causing variant on one or both alleles, fingerprint bodies, or lymphocytic vacuoles. ** Classic JNCL phenotype as defined by age-at-onset of core features of the disease as well as progression of the disease. *** Without diagnostic evidence and with an atypical phenotype, further investigation is necessary to determine if the individual has CLN3 disease, a different NCL, or a different diagnosis entirely)
See this image and copyright information in PMC

References

    1. Claussnitzer M, Cho JH, Collins R, et al. A brief history of human disease genetics. Nature. 2020;577(7789):179–189. - PMC - PubMed
    1. Marshall CR, Chowdhury S, Taft RJ, et al. Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease. NPJ Genom Med. 2020;5:47. - PMC - PubMed
    1. Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology. 2012; 79(2):183–191. - PubMed
    1. Zhong N, Moroziewicz DN, Ju W, et al. Heterogeneity of late-infantile neuronal ceroid lipofuscinosis. Genet Med. 2000;2(6): 312–318. - PubMed
    1. Augustine EF, Adams HR, Beck CA, et al. Standardized assessment of seizures in patients with juvenile neuronal ceroid lipofuscinosis. Dev Med Child Neurol. 2015;57(4):366–371. - PMC - PubMed

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