Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families

Abstract

Purpose Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. Methods The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. Results Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. Conclusion Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.

TUBB3 and KIF21A in neurodevelopment and disease

“…Human KIF21A variants Below, we review the phenotypes reported with specific KIF21A variants, as summarized in Figure 5 and Table 4. (Yamada et al, 2003(Yamada et al, , 2004(Yamada et al, , 2005Chan et al, 2007;Lu et al, 2008;Yang et al, 2010;Wang et al, 2011;Al-Haddad et al, 2021;Moon et al, 2021;Jia et al, 2022;Chen et al, 2023). These heterozygous missense variants in KIF21A occur in association with CFEOM and were first reported in 2003 (Yamada et al, 2003).…”