Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype-phenotype relationships

Hum Mutat. 2022 Dec;43(12):2141-2152. doi: 10.1002/humu.24483. Epub 2022 Oct 17.


ADAMTSL4 variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma. However, a genotype-phenotype correlation has not been established. Potentially pathogenic ADAMTSL4 variants were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing followed by multiple bioinformatics analyses. The genotype-phenotype correlation was assessed via a systematic review of ADAMTSL4 variants within our data and those from the literature. A total of 12 variants of ADAMTSL4, including seven frameshift variants, one nonsense variant, two splicing variants, and two missense variants, were found in nine probands. Combing genetic and clinical information from 72 probands in the literature revealed 37 ADAMTSL4 variants known to cause EL, and the ethnic difference was prominent. The lens was inclined to dislocate inferior temporally (22, 27.16%), while the pupil was always located oppositely (9, 81.82%). Several anterior segments anomalies were identified, including ectopia pupillae (15, 18.52%), persistent pupillary membrane (9, 11.10%), poor pupil dilation (4, 30.8%), cataract (13, 24.10%), and glaucoma (8, 13.33%). Genotype-phenotype analysis revealed that truncation variants had higher risks of combined iris anomalies, including either ectopia pupillae or a persistent pupillary membrane (p = 0.007). The data from this study not only extend our knowledge of the ADAMTSL4 variant spectrum but also suggest that deleterious variants of ADAMTSL4 might be associated with severe ocular phenotypes.

Keywords: ADAMTSL4; corectopia; ectopia lentis; genotype-phenotype correlation; persistent pupillary membrane.

Publication types

  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / genetics
  • Cataract* / genetics
  • East Asian People
  • Ectopia Lentis* / genetics
  • Ectopia Lentis* / pathology
  • Glaucoma*
  • Humans
  • Mutation
  • Pedigree


  • ADAMTS Proteins
  • ADAMTSL4 protein, human

Supplementary concepts

  • Ectopia pupillae