A microdeletion in the GRHL2 Gene in two unrelated patients with congenital fibrosis of the extra ocular muscles

Abstract

Objective: Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is known to be caused by mutations in KIF21A or TUBB3 or other known genes (SALL4, CHN1, HOXA1). However, affected children may harbor other genetic defects. Therefore, a candidate gene analysis (KIF21A, TUBB3 SALL4, CHN1, HOXA1) and a high-resolution array comparative genomic hybridization (arrayCGH) was performed in two unrelated children with sporadic CFEOM1.

Results: Two unrelated Saudi patients did not have any mutation(s) after sequencing the full coding regions of SALL4, CHN1, HOXA1, and TUBB3 genes; and exons 8, 20, and 21 of the KIF21A gene. However, arrayCGH revealed a 3.17 Kb deletion at chromosome 8p22 with copy number state equal to 1, indicating a heterozygous deletion. This deletion was absent in proband's mother or father or 220 unrelated healthy individuals of similar ethnicity. The deletion encompassed only one functional gene, GRHL2, which encodes a transcription factor. In humans, defects in this gene are a cause of non-syndromic sensorineural deafness, autosomal dominant type 28 (DFNA28). We speculate that GRHL2 gene may have a role in orbital innervations and the defect in this gene (deletion) may be related to the CFEOM1 phenotype in these two children.

Keywords: CCDD; Congenital fibrosis; GRHL2; arrayCGH.

Fig. 1

a (Patient 1) this 5-year old girl adopted a chinup position to compensate for her bilateral hypotropia, elevation deficiency, and ptosis. She also preferred a left face turn to fixate with her preferred right eye. With her compensatory head position there is a moderate left exotropia. b (Patient 2) this 22 month old boy adopted a chin-up position to compensate for his bilateral hypotropia, elevation deficiency, and ptosis. With his compensatory head position there was no horizontal strabismus