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A diagnostic confidence scheme for CLN3 disease
Author(s) -
Masten Margaux C.,
Corre Camille,
Paciorkowski Alex R.,
Vierhile Amy,
Adams Heather R.,
Vermilion Jennifer,
Zimmerman Grace A.,
Augustine Erika F.,
Mink Jonathan W.
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12429
Subject(s) - phenotype , disease , confidence interval , genetic testing , biology , genetics , medicine , bioinformatics , pathology , gene
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.