Genomic landscape and mutational spectrum of ADAMTS family genes in mendelian disorders based on gene evidence review for variant interpretation

John Hoon Rim, Yo Jun Choi, Heon Yung Gee

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1 Citation (Scopus)


ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various hereditary diseases. To understand the genomic landscape and mutational spectrum of ADAMTS family genes, we evaluated all reported variants in the ClinVar database and Human Gene Mutation Database (HGMD), as well as recent literature on Mendelian hereditary disorders associated with ADAMTS family genes. Among 1089 variants in 14 genes reported in public databases, 307 variants previously suggested for pathogenicity in Mendelian diseases were comprehensively re-evaluated using the American College of Medical Genetics and Genomics (ACMG) 2015 guideline. A total of eight autosomal recessive genes were annotated as being strongly associated with specific Mendelian diseases, including two recently discovered genes (ADAMTS9 and ADAMTS19) for their causality in congenital diseases (nephronophthisis-related ciliopathy and nonsyndromic heart valve disease, respectively). Clinical symptoms and affected organs were extremely heterogeneous among hereditary diseases caused by ADAMTS family genes, indicating phenotypic heterogeneity despite their structural and functional similarity. ADAMTS6 was suggested as presenting undiscovered pathogenic mutations responsible for novel Mendelian disorders. Our study is the first to highlight the genomic landscape of ADAMTS family genes, providing an appropriate genetic approach for clinical use.

Original languageEnglish
Article number449
Issue number3
Publication statusPublished - 2020 Mar

Bibliographical note

Funding Information:
Funding: H.Y.G. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning [2018R1A2A3074572].

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Th.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology


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