Genotype Phenotype Correlation and Variability in Microcephaly Associated With Chorioretinopathy or Familial Exudative Vitreoretinopathy

Abstract

Purpose The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11 , TUBGCP4 , or TUBGCP6. Methods Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression. Results Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients. Conclusions Microcephaly due to mutations in KIF11 , TUBGCP4 , or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.

Genotype-phenotype associations in familial exudative vitreoretinopathy: A systematic review and meta-analysis on more than 3200 individuals

“…Previous studies [ 44 – 46 ] have found that FEVR patients of the same family and genetic mutation have different clinical manifestations. These studies believed that there was no correlation between gene mutation types and clinical phenotype [ 25 ].…”

Retinal Features of Family Members With Familial Exudative Vitreoretinopathy Caused By Mutations in KIF11 Gene

“…There have been a few studies that reported that eyes with KIF11 mutations had incomplete vascularization of the peripheral retina whereas the majority of studies on MCLMR did not report signs of FEVR except for retinal folds. 20 , 37 , 42 The severity of FEVR is generally highly variable although peripheral avascularization is believed to be a consistent sign. However, the presence of peripheral avascularization alone is ambiguous for diagnosing FEVR as it is also present in some eyes of normal subjects and other retinal diseases.…”

“…The combination of the systemic features is consistent with the autosomal recessive microcephaly and chorioretinopathy that is caused by mutations in the TUBGCP4 , TUBGCP6, and PLK4 genes. 42 , 48 , 49 These genes share the physiological role in the mitotic spindle with KIF11, and microcephaly and chorioretinopathy is indeed indistinguishable from MCLMR except for the mode of inheritance. 34 , 39 The term of FEVR tends to be applied to congenital RDs with ischemic vitreoretinal proliferation as a replacement of other terms of congenital retinal folds (falciform retinal folds), posterior hyperplastic primary vitreous, pseudoglioma, and congenital retinal nonattachment.…”

Kinesin-5 Eg5 is essential for spindle assembly, chromosome stability and organogenesis in development

“…In human patients, the individuals with mutations of Eg5 show severe microcephaly, bilateral chorioretinopathy, and developmental delay, including a thin body [ 21 ] and growth retardation [ 22 ]. Lymphedema in patients is present at birth and is usually restricted to both lower limbs [ 19 , 20 ].…”

“…In humans, Eg5 proteins are located at the inner segments and ciliary compartments of photoreceptors and in the retinal pigment epithelium [ 46 ]. The Eg5-associated disease represents a potential system ciliopathy with defects in photoreceptor development and retinal angiogenesis [ 22 , 46 ]. The Eg5 vascular endothelial cell-specific knockout mouse models suggest that the Eg5 -deficient retinal vascular phenotype is independent of the established Norrin Wnt β-catenin signaling pathway [ 54 , 55 ].…”