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

Area of Science:

• Ophthalmology
• Medical Genetics
• Molecular Biology

Background:

• Congenital microcephaly is a complex condition with diverse genetic underpinnings.
• Ocular manifestations, including chorioretinopathy and familial exudative vitreoretinopathy (FEVR), can co-occur with microcephaly.
• Specific gene mutations are increasingly identified as causative for syndromic microcephaly with ocular findings.

Purpose of the Study:

• To investigate the natural history and phenotypic spectrum of microcephaly associated with mutations in KIF11, TUBGCP4, or TUBGCP6.
• To analyze the overlap between chorioretinopathy and FEVR phenotypes in these patients.
• To understand the progression of ocular disease in individuals with these specific genetic variants.

Main Methods:

• Retrospective analysis of 12 patients from 9 families diagnosed with congenital microcephaly and ocular findings.
• Targeted genetic sequencing to identify mutations in KIF11, TUBGCP4, and TUBGCP6.
• Comprehensive review of medical records, ophthalmic examinations, imaging, electroretinography, and visual field data.

Main Results:

• Nine patients harbored KIF11 variants, two had TUBGCP6 variants, and one had TUBGCP4 variants.
• All patients exhibited reduced visual function, with phenotypes spanning chorioretinopathy and FEVR.
• Posterior segment disease progression, including macular/retinal atrophy and vitreoretinal traction, was observed in 9 of 12 patients over an 8-year follow-up.

Conclusions:

• Mutations in KIF11, TUBGCP4, or TUBGCP6 are associated with microcephaly and a spectrum of retinal diseases, from chorioretinal atrophy to FEVR.
• Significant visual progression can occur, necessitating vigilant monitoring.
• Ophthalmic genetics expertise is crucial for managing these patients.