Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

Abstract

Microphthalmia, anophthalmia, and coloboma (MAC) are a group of congenital eye anomalies that can affect one or both eyes. Patients can present one or a combination of these ocular abnormalities in the so called "MAC spectrum". The KIF17 gene encodes the kinesin-like protein Kif17, a microtubule-based, ATP-dependent, motor protein that is pivotal for outer segment development and disc morphogenesis in different animal models, including mice and zebrafish. In this report, we describe a Sicilian family with two siblings affected with congenital coloboma, microphthalmia, and a mild delay of motor developmental milestones. Genomic DNA from the siblings and their unaffected parents was sequenced with a clinical exome that revealed compound heterozygous variants in the KIF17 gene (NM_020816.4: c.1255C > T (p.Arg419Trp); c.2554C > T (p.Arg852Cys)) segregating with the MAC spectrum phenotype of the two affected siblings. Variants were inherited from the healthy mother and father, are present at a very low-frequency in genomic population databases, and are predicted to be deleterious in silico. Our report indicates the potential co-segregation of these biallelic KIF17 variants with microphthalmia and coloboma, highlighting a potential conserved role of this gene in eye development across different species.

Keywords: KIF17; MAC spectrum; coloboma; congenital eye defects; microphthalmia.

Figure 1

Family tree, KIF17 protein structure, and the clinico-radiological features of our siblings. (A) Pedigree from family. (B) KIF17 protein structure with domains and the two pathogenic variants found in our probands. (C) Clinico-radiological findings of Patient II-1. (C′) Image of eyes showing left microphthalmia at age. (C″) Brain MRI at age 7 months. Axial FLAIR images demonstrate bilateral focal posterior defects of the globes with vitreous herniation suggestive for bilateral posterior coloboma. In the left eye a fluid-density cist is also present (white arrow). (D) Clinico-radiological features of Patient II-2. (D′) Image of eyes showing left microphthalmia at age. (D″) Additional eye images taken at age. (D‴) Brain MRI at age 5 months. Axial T2-weighted image showing right “egg shaped” globe suggestive for posterior coloboma. In the left eye the “egg shape” is less deducible due to microphthalmia, as well as lens luxation.

Figure 2

(A) KIF17 gene expression in the different eye-related cell types based on the Human Protein Atlas (www.proteinatlas.org, accessed on 21 April 2021). (B) Multiple alignment showing complete conservation across species and KIF17 homolog of the residues affected by the variants identified in this study (these variants are highlighted in yellow). Human KIF17 (UniProt: Q9P2E2), Chimpanzee KIF17 (UniProt: H2PY89), Horse KIF17 (UniProt: F6VCL8), Cat KIF17 (UniProt: A0A2I2V0D2), Mouse KIF17 (UniProt: Q99PW8), Zebrafish KIF17 (UniProt: F1QV34).