Genotype–phenotype spectrum in isolated and syndromic nanophthalmos

Abstract

Purpose 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 MFRP variants, based on a detailed literature review of genotype–phenotype correlations. Methods 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 MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF and FAM111A. A minigene assay was performed for functional characterization of a splice site variant. Results Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants in MFRP (c.497C>T, c.899‐3C>A, c.1180G>A), and PRSS56 (c.1202C>A), and a recurrent de novo variant in FAM111A (c.1706G>A) in a patient with Kenny–Caffey syndrome type 2, were identified. In addition, we report co‐inheritance of MFRP‐related nanophthalmos and ADAR‐related Aicardi–Goutières syndrome. Conclusion 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 MFRP variants. Furthermore, heterozygous carriers of MFRP and PRSS56 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.

A Novel Mutation in the Membrane Frizzled-Related Protein Gene for Posterior Microphthalmia, Non-pigmented Retinitis Pigmentosa, Optic Nerve Drusen, and Retinoschisis in a Consanguineous Family

“…Congenital microphthalmia (MCO) is a heterogeneous developmental eye disease characterized by small, hyperopic eyes secondary to several etiological factors affecting the early formation of the eye ( 4 ). MCO may be isolated, complex, or syndromic based on the presence or absence of associated systemic involvement.…”

“…Additional characteristics are a narrow angle between the iris and cornea, expansion of the choroidal vascular bed underlying the retinal pigment epithelium (RPE) and thickening of the scleral connective tissue surrounding the eye. Retinoschisis and OND were not always part of the phenotype in all cases ( 4 ), and some patients with MFRP mutation presented microphthalmia but no fundoscopic changes ( 23 ). It is well-known that papillomacular retinal folds frequently develop in subjects with nanophthalmos or microphthalmos, presumably arising from a disparity in growth between the sclera and retina and impaired vision.…”

“…These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as non-syndromic or isolated ( 4 ). MCO can be divided into two clinical subtypes called nanophthalmos (NNO) and posterior microphthalmia (MCOP), and nanophthalmos is classically distinguished from posterior microphthalmia based on the presence of normal corneal size and anterior chamber dimensions ( 5 ).…”

“…MFRP gene mutations causing photoreceptor degeneration and RPE atrophy have been reported in mice ( 12 ). Considerable phenotypic variability was observed in microphthalmia with no clear genotype-phenotype correlations ( 4 , 16 ). Moreover, the rare association of nanophthalmos/microphthalmos with pigmentary retinal dystrophy has been described in the literature in 1958 ( 17 ).…”

Ablation of mpeg+ Macrophages Exacerbates mfrp-Related Hyperopia

“…Although variants in many genomic regions are associated with changes in refractive error, variants in just a few genes have been associated with monogenic high hyperopia or nanophthalmos. 1 – 4 Homozygous or compound heterozygous mutations of MFRP , which encodes membrane-type frizzled-related (MFRP) protein, are associated with microphthalmia, high hyperopia, foveoschisis, areas of retinal pigmented epithelium (RPE) atrophy, and optic disc drusen in humans. 1 , 2 , 5 – 11 Evidence for the conservation of MFRP function comes from multiple animal models.…”