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Yi Liang, Hongyan Jia, Yulan Liang, Hui Wang, Yonghong Jiao; Efficient High-Throughput Targeted Exome Sequencing Kit for Differential Diagnosis of Congenital Special Forms of Strabismus. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6046.
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Congenital special forms of strabismus (CSS) are a group of clinically heterogeneous diseases, which are considered to be neuropathic or myopathic, such as congenital cranial dysinnervation disorder (CCDDs), muscle-eye-brain disease (MEB) and core myopathies. This type of disease is very ideal to examine the pathogenesis of cerebral motor nerve dysplasia. Since different CSS related diseases usually have overlapping clinical features, we aimed to establish an effective molecular diagnosis kit based on high-throughput candidate gene targeted exome sequencing, which can guide clinicians to make more accurate diagnoses of disease subtypes.
Forty-four patients with CSS were enrolled in the study (20 were familial and 24 were sporadic) ranged from 3-55 years old, 28 (M) and 16(F). All patients underwent comprehensive ophthalmic examinations and MRI of the orbits and brain stem. A total of 115 genes had been pre-selected based on the literature search from PUBMED, which are known to be involved in the occurrence of CCDDs, congenital ptosis, external ophthalmoplegia, congenital myopathy, and congenital anomalies of limb. The exome sequencing data of these preselected genes of the studied patients were obtained and further analyzed using the established bioinformatics pipeline. The findings of the nucleotide variations were validated in the family members and 100 unrelated normal individuals using Sanger sequencing.
Ten mutations in 5 genes were identified, which include KIF21A（3 mutations in 19 probands,）TUBB3（3 mutations in 8 probands）, POMGNT1（2 mutations in 2 probands）, RYR1（1 mutation in 1 proband） and CHN1 (1 mutation in 1 proband）. 70.5% of probands (31/44) were able to correctly diagnosed using the identified genes. Further MRI examinations of these patients showed marked hypoplasia of corresponding extraocular muscles and abnormality of cranial innervation. With MRI, 27 patients were diagnosed with CFEOM, 2 patients were diagnosed with MEB, 1 patient diagnosed with Duane syndrome, and 1 patient diagnosed with multi-minicore disease.
We established a high sensitivity and specificity gene diagnosis kit for CSS based on targeted exome sequencing, which could be employed as a rapid, cost-efficient method for the routine genetic diagnosis of congenital special forms of strabismus.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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