Clinical characteristics of a KIF21A mutation in a Chinese family with congenital fibrosis of the extraocular muscles type 1

Abstract

The aim of the study is to characterize the clinical ocular phenotype with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) and to confirm whether the kinesin family member 21A (KIF21A) mutation was the pathogenic gene in this Chinese family.Three affected individuals and 2 asymptomatic kinsfolk from a Chinese family underwent comprehensive ophthalmic examinations, orbital computerized tomography (CT), and postoperative histological examinations were performed in the proband. All the recruited members were screened for 3 exons (8, 20, and 21) of KIF21A mutations using the polymerase chain reaction (PCR) amplification and direct sequencing of corresponding PCR products.All patients shared the clinical characteristics including bilateral ophthalmoplegia, blepharoptosis, hypertropic, and exotropic position with inability to raise either eye above the midline and a chin-up head position. Direct DNA sequence analysis from the affected members revealed a missense mutation in KIF21A (c.2860C>T, p.R954W). The unaffected members did not harbor the p.R954W mutation. The candidate mutation was not present in multiple web-accessible and in-house exome databases.The p.Arg954Trp mutation of KIF21A was the causative mutation in this Chinese pedigree with CFEOM1.

Figure 1

Pedigree of a Chinese family affected with CFEOM1. Normal individuals are shown as empty symbols. Affected males and females are indicated by filled-in squares and circles, respectively. The proband of the pedigree is indicated by an arrow. Deceased individuals are indicated by a slash (/). The normal individual who lost contact with her family at 4 years old is indicated by a question mark (?). The affected male who was unable to be examined due to his occupation as a migrant worker is indicated by octothorpe (#). CFEOM1 = congenital fibrosis of the extraocular muscles type 1.

Figure 2

Photographs of the proband. Photographs were taken in the primary position (E) and the 8 cardinal gaze positions (A, B, C, D, F, G, H, and I). The photos show typical ophthalmoplegia, hypertropia, and exotropia in the primary position with the inability to raise either eye above the horizontal midline. This patient also had ptosis in both eyes (not shown).

Figure 3

Postoperation photographs of the proband's vertical strabismus diorthosis and horizontal strabismus diorthosis. After surgery, the primary position of the fixating eye shows no deviation with a 15° to 20° horizontal deviation of the other eye (A). The upper eyelid margin reached the upper edge of the pupil with reduced chin-up head position (B).

Figure 4

Photographs of postoperative histological examination. Bilateral superior recti showed atrophy and fibrosis. Vascular proliferation, hemorrhage, and hyperemia were observed in local areas (A). An increase in myocyte nuclei was also found (B).

Figure 5

Photographs of Patient I:1 and Patient II:4. Photos of Patient I:1 were taken in primary gaze (A and B). Photos of Patient II:4 were taken in primary gaze (C and D), in right gaze (E), and left gaze (F).

Figure 6

Gene sequence analysis. The gene sequences from the proband, Patient I:1, and Patient II:4 (A, B, and C, respectively). Analysis showed c.2860C>T mutation. Normal gene sequences were obtained from Individual II:5 and Individual III:3 (D and E, respectively).