NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp) AND Fibrosis of extraocular muscles, congenital, 3b

Significance: Pathogenic
ClinVar: RCV000002539

Variant: NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp)

Type: Variant
Allele: NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp) 17475
Type: single nucleotide variant
Location: Chr12: 39332405 - assembly GRCh38
Chr12: 39726207 - assembly GRCh37
References: dbSNP: 121912585
OMIM: 608283.0001
UniProtKB: Q7Z4S6#VAR_019403


Disease: Fibrosis of extraocular muscles, congenital, 3b


    In patients with congenital fibrosis of extraocular muscles-1 (135700), Yamada et al. (2003) identified a C-to-T transition at nucleotide 2860 of the KIF21A gene, resulting in an arg954-to-trp (R954W) substitution. R954W was the most frequent mutation in the KIF21A gene identified as the cause of FEOM1 by Yamada et al. (2003). Yamada et al. (2003) published a picture of a child with FEOM1 who harbored the R954W mutation and had bilateral ptosis and bilateral infraducted (downward) eye position in primary gaze with a chin-up head posture. She could not raise either eye above the neckline.
    Tiab et al. (2004) identified this mutation in 3 familial cases of CFEOM1 in patients of Swiss, Turkish, and French origin, respectively, and in a sporadic case in an Iranian patient. Ali et al. (2004) identified this mutation in affected members of a 4-generation Indian family with FEOM1. Ali et al. (2004) concluded that the high mutability of this CpG dinucleotide (see also 608283.0002) may result, in part, from its methylated state.
PMID:15621876, PMID:15621877
    Lin et al. (2005) identified a heterozygous R943W mutation in affected members of 2 Taiwanese families with classic CFEOM1 and an unrelated Taiwanese patient with sporadic CFEOM1. Affected members of a third Taiwanese family with a diagnosis of CFEOM3 (CFEOM3B; see 135700) were also found to carry the heterozygous mutation. The phenotype in the third family was considered different because of intrafamilial variation in disease severity. Two members had classic disease with severe ptosis and fixed eyes. Three other members were all affected, but these individuals could still move their eyes, and severity between the 2 eyes also differed. The molecular findings indicated that the CFEOM3 phenotype can be caused by KIF21A mutations, and that the expression of KIF21A mutations may be variable. In fact, Lin et al. (2005) even suggested that the third family may be better described as CFEOM1 with variability in expression.
    Rudolph et al. (2009) reported 3 families and 2 unrelated patients with CFEOM1 due to a heterozygous R943W mutation. All patients were of German origin, except 1 who was Turkish. The phenotype was relatively homogeneous: affected individuals showed bilateral restricted upgaze with compensatory chin elevation, ptosis, and variable limitations of horizontal gaze motility. Some had esotropia and/or exotropia. Many patients had corrective surgery of the extraocular muscles. In 1 family, affected individuals also had mental disability or mental retardation, which Rudolph et al. (2009) postulated may indicate that the syndrome can be associated with more general neurologic dysfunction in addition to impairment in ocular motility. Haplotype analysis did not indicate a founder effect.