title: Frizzled-4 Variations Associated with Retinopathy and Intrauterine Growth Retardation: A Potential Marker for Prematurity and Retinopathy.
abstract: OBJECTIVE
  To present the association between mutations affecting the Wnt-signaling receptor protein (FZD4), inherited vitreoretinopathies, and retinopathy of prematurity (ROP).
  
  
  METHODS
  Retrospective analysis of prospective samples at a tertiary referral center.
  
  
  METHODS
  Patients referred to our practice for management of a variety of pediatric vitreoretinopathies were offered participation in an ophthalmic biobank (421 participants with vitreoretinopathies were included in this study). Full-term healthy infants (n = 98) were recruited to the study as controls.
  
  
  METHODS
  Patients with various vitreoretinopathies were prospectively enrolled in an ophthalmic biobank, approved by the Human Investigation Committee at William Beaumont Hospital. Retrospective genetic analysis of the FZD4 gene was performed (Sanger sequencing). Participants with a diagnosis of familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats' disease, bilateral persistent fetal vasculature, and ROP were reviewed for the presence of a FZD4 variant. Data retrieval included status of retinopathy (including staging when possible), gestational age (GA), birth weight (BW) (when available), and family and birth histories.
  
  
  METHODS
  The association of FZD4 variants with the presence of vitreoretinopathy.
  
  
  RESULTS
  The sequence variation p.[P33S(;)P168S] is the most prevalent FZD4 variant and is statistically significant for ROP and FEVR (P = 4.6E-04 and P = 2.4E-03, respectively) compared with full-term newborns (P = 1.7E-01). In addition, infants expressing the sequence variation tended to have significantly lower BWs for respective GA (P = 0.04). This suggests that the FZD4 p.[P33S(;)P168S] variant may be a risk factor for retinopathy and restricted intrauterine growth.
  
  
  CONCLUSIONS
  Testing for FZD4 gene mutations is useful in patients with suspected FEVR and ROP. The relatively high prevalence of the p.[P33S(;)P168S] variant in ROP and intrauterine growth restriction suggests that it also may be a marker for increased risk of developing ROP and preterm birth.
authors.affiliation: Research Institute, William Beaumont Hospital, Royal Oak, Michigan.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Dailey
authors.affiliation: Eye Research Institute, Oakland University, Rochester, Michigan.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Gryc
authors.affiliation: Research Institute, William Beaumont Hospital, Royal Oak, Michigan.
authors.forename: Pooja G
authors.initials: PG
authors.lastname: Garg
authors.affiliation: Associated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan. Electronic address: kdrenser@arcpc.net.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Drenser
mesh_terms: D018070:Biological Specimen Banks; D001724:Birth Weight; D001766:Blindness / Q000151:congenital / Q000235:genetics; D015785:Eye Diseases, Hereditary; D000080345:Familial Exudative Vitreoretinopathies; D005317:Fetal Growth Retardation / Q000235:genetics*; D051157:Frizzled Receptors / Q000235:genetics*; D040181:Genetic Diseases, X-Linked; D005819:Genetic Markers; D014644:Genetic Variation; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics; D009422:Nervous System Diseases / Q000235:genetics; D054514:Persistent Hyperplastic Primary Vitreous / Q000235:genetics; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012162:Retinal Degeneration; D012164:Retinal Diseases / Q000235:genetics; D058456:Retinal Telangiectasis / Q000235:genetics; D012178:Retinopathy of Prematurity / Q000235:genetics*; D012189:Retrospective Studies; D013036:Spasms, Infantile / Q000235:genetics
chemical_list: C402930:FZD4 protein, human; D051157:Frizzled Receptors; D005819:Genetic Markers