Genotype–phenotype spectrum in isolated and syndromic nanophthalmos

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  • Elena Lang
    Department of Ophthalmology University Hospital Zurich and University of Zurich Zurich Switzerland
  • Samuel Koller
    Institute of Medical Molecular Genetics University of Zurich Schlieren Switzerland
  • David Atac
    Institute of Medical Molecular Genetics University of Zurich Schlieren Switzerland
  • Oliver A. Pfäffli
    Department of Ophthalmology University Hospital Zurich and University of Zurich Zurich Switzerland
  • James V.M. Hanson
    Department of Ophthalmology University Hospital Zurich and University of Zurich Zurich Switzerland
  • Silke Feil
    Institute of Medical Molecular Genetics University of Zurich Schlieren Switzerland
  • Luzy Bähr
    Institute of Medical Molecular Genetics University of Zurich Schlieren Switzerland
  • Angela Bahr
    Institute of Medical Genetics University of Zurich Zurich Switzerland
  • Raimund Kottke
    Department of Diagnostic Imaging University Children's Hospital Zurich Zurich Switzerland
  • Pascal Joset
    Institute of Medical Genetics University of Zurich Zurich Switzerland
  • Katrin Fasler
    Department of Ophthalmology University Hospital Zurich and University of Zurich Zurich Switzerland
  • Daniel Barthelmes
    Department of Ophthalmology University Hospital Zurich and University of Zurich Zurich Switzerland
  • Katharina Steindl
    Institute of Medical Genetics University of Zurich Zurich Switzerland
  • Daniel Konrad
    Department of Pediatric Endocrinology and Diabetology University Children’s Hospital Zurich Switzerland
  • David‐Alexander Wille
    Department of Pediatric Neurology University Children’s Hospital Zurich Switzerland
  • Wolfgang Berger
    Institute of Medical Molecular Genetics University of Zurich Schlieren Switzerland
  • Christina Gerth‐Kahlert
    Department of Ophthalmology University Hospital Zurich and University of Zurich Zurich Switzerland

Description

<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their functional characterization and (ii) to study the association of retinal dystrophy in patients with <jats:italic>MFRP</jats:italic> variants, based on a detailed literature review of genotype–phenotype correlations.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Patients with nanophthalmos and available family members received a comprehensive ophthalmological examination. Genetic analysis was based on whole‐exome sequencing and variant calling in core genes including <jats:italic>MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF</jats:italic> and <jats:italic>FAM111A</jats:italic>. A minigene assay was performed for functional characterization of a splice site variant.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants in <jats:italic>MFRP</jats:italic> (c.497C>T, c.899‐3C>A, c.1180G>A), and <jats:italic>PRSS56</jats:italic> (c.1202C>A), and a recurrent de novo variant in <jats:italic>FAM111A</jats:italic> (c.1706G>A) in a patient with Kenny–Caffey syndrome type 2, were identified. In addition, we report co‐inheritance of <jats:italic>MFRP</jats:italic>‐related nanophthalmos and <jats:italic>ADAR</jats:italic>‐related Aicardi–Goutières syndrome.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenic <jats:italic>MFRP</jats:italic> variants. Furthermore, heterozygous carriers of <jats:italic>MFRP</jats:italic> and <jats:italic>PRSS56</jats:italic> should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.</jats:p></jats:sec>

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