title: ADAMTSL4 assessment in ectopia lentis reveals a recurrent founder mutation in Polynesians.
abstract: To clinically characterize a cohort of patients with ectopia lentis (EL), or Marfanoid features in whom a definite genetic diagnosis of Marfan syndrome (MFS) had been excluded (atypical MFS), and to evaluate the contribution of mutations in ADAMTSL4 (OMIM * 610113), and P3H2 (LEPREL1; OMIM * 610341) to disease in this population.
  
  
  
  Subjects underwent comprehensive ophthalmic examination, including keratometry. Mutational analysis of ADAMTSL4 and P3H2 was undertaken using PCR, high resolution melting analysis, and sequencing. The frequency of c.2237G>A; p.(Arg746His) was determined in an unaffected Polynesian cohort. Haplotype analysis used tagged single nucleotide polymorphic markers.
  
  
  
  Mutational analysis of ADAMTSL4 identified two pathogenic variants in ADAMTSL4 in 11/31 (35%) probands, consistent with the autosomal recessive EL phenotype. A recurrent, rare missense variant in ADAMTSL4, c.2237G>A; p.(Arg746His), was present in 10 probands -(8 homozygotes), predominantly of Polynesian descent, and all shared the same haplotype. p.(Arg746His) affects the Thrombospondin1 (TSP1) domain of the protein and is predicted to be pathogenic. No pathogenic variants in P3H2 were identified.
  
  
  
  A recurrent pathogenic ADAMTSL4 variant is a major cause of early onset autosomal recessive EL in a Cook Island Māori population and associated with a common haplotype, suggesting a founder effect. Children presenting under the age of 5 years, particularly of Cook Island or New Zealand Māori descent, with isolated ectopia lentis, should in the first instance be tested for this single variant.
authors.affiliation: a Department of Ophthalmology, FMHS, New Zealand National Eye Centre , University of Auckland , Auckland , New Zealand.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: van Bysterveldt
authors.affiliation: a Department of Ophthalmology, FMHS, New Zealand National Eye Centre , University of Auckland , Auckland , New Zealand.|b Department of Ophthalmology, Manukau SuperClinic , Counties Manukau District Health Board , Auckland , New Zealand.
authors.forename: Rasha
authors.initials: R
authors.lastname: Al Taie
authors.affiliation: a Department of Ophthalmology, FMHS, New Zealand National Eye Centre , University of Auckland , Auckland , New Zealand.
authors.forename: Will
authors.initials: W
authors.lastname: Ikink
authors.affiliation: a Department of Ophthalmology, FMHS, New Zealand National Eye Centre , University of Auckland , Auckland , New Zealand.
authors.forename: Verity F
authors.initials: VF
authors.lastname: Oliver
authors.affiliation: a Department of Ophthalmology, FMHS, New Zealand National Eye Centre , University of Auckland , Auckland , New Zealand.|c Eye Department, Greenlane Clinical Centre , Auckland District Health Board , Auckland , New Zealand.
authors.forename: Andrea L
authors.identifier: 0000-0002-4185-3267
authors.initials: AL
authors.lastname: Vincent
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004479:Ectopia Lentis / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D009520:New Zealand; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011114:Polynesia; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics; D011446:Prospective Studies
chemical_list: C486779:ADAMTSL4 protein, human; D011393:Procollagen-Proline Dioxygenase; C568061:P3H2 protein, human; D000071096:ADAMTS Proteins
keywords: ADAMTSL4; Marfan syndrome; ectopia lentis