A novel deep intronic variant strongly associates with Alkaptonuria

Chien-Yi Lai; I-Jung Tsai; Pao-Chin Chiu; David B Ascher; Yin-Hsiu Chien; Yu-Hsuan Huang; Yi-Lin Lin; Wuh-Liang Hwu; Ni-Chung Lee

doi:10.1038/s41525-021-00252-2

A novel deep intronic variant strongly associates with Alkaptonuria

NPJ Genom Med. 2021 Oct 22;6(1):89. doi: 10.1038/s41525-021-00252-2.

Authors

Chien-Yi Lai^{1

2

3}, I-Jung Tsai², Pao-Chin Chiu⁴, David B Ascher^{5

6

7

8}, Yin-Hsiu Chien^{1

2}, Yu-Hsuan Huang¹, Yi-Lin Lin¹, Wuh-Liang Hwu^{1

2}, Ni-Chung Lee^{9

10}

Affiliations

¹ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Pediatrics, National Taiwan University Children Hospital, Taipei, Taiwan.
³ Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan.
⁴ Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁵ Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
⁶ Structural Biology and Bioinformatics, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, VIC, Australia.
⁷ Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia.
⁸ Department of Biochemistry, Bio21 Institute, University of Cambridge, Cambridge, UK.
⁹ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. ncleentu@ntu.edu.tw.
¹⁰ Department of Pediatrics, National Taiwan University Children Hospital, Taipei, Taiwan. ncleentu@ntu.edu.tw.

Abstract

Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardiac valvular calcification, and urolithiasis. The epidemiology of alkaptonuria in East Asia is not clear. In this study, patients diagnosed with alkaptonuria from January 2010 to June 2020 were reviewed. Their clinical and molecular features were further compared with those of patients from other countries. Three patients were found to have alkaptonuria. Mutation analyses of the homogentisate 1,2-dioxygenase gene (HGD) showed four novel variants c.16-2063 A > C, p.(Thr196Ile), p.(Gly344AspfsTer25), and p.(Gly362Arg) in six mutated alleles (83.3%). RNA sequencing revealed that c.16-2063 A > C activates a cryptic exon, causing protein truncation p.(Tyr5_Ile6insValTer17). A literature search identified another 6 patients with alkaptonuria in East Asia; including our cases, 13 of the 18 mutated alleles have not been reported elsewhere in the world. Alkaptonuria is rare in Taiwan and East Asia, with HGD variants being mostly novel and private.

Abstract

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