Whole Exome Sequencing as an Effective Molecular Diagnosis Tool for Craniofacial Fibrous Dysplasia with Ocular Complications

Abstract

Purpose

To summarize the clinical manifestations of craniofacial fibrous dysplasia (CFD) patients with ocular complications, and find effective methods to diagnose early.

Methods

Nine CFD patients with ocular complications, and their parents were recruited in this study. All patients underwent ocular and systemic examinations. Bone lesions from all patients and peripheral blood from patients and their parents were collected for whole exome sequencing (WES). According to the screening for low-frequency deleterious variants, and bioinformatics variants prediction software, possible disease-causing variants were found in multiple CFD patients. The variants were validated by Sanger sequencing. Trio analysis was performed to verify the genetic patterns of CFD.

Results

All patients were diagnosed with CFD, according to the clinical manifestations, classic radiographic appearance, and pathological biopsy. The main symptoms of the 9 CFD patients, included visual decline (9/9), craniofacial deformity (3/9) and strabismus (2/9), with few extraocular manifestations. The family backgrounds of all the CFD patients indicated that only the patient was affected, and their immediate family members were normal. GNAS variants were identified in all bone lesions from CFD patients, including two variant types: c.601C > T:p.R201C(6/9) and c.602G > A:p.R201H (3/9) in exon 8. The detection rate reached 100% by WES, but only 77.8% by Sanger sequencing. Interestingly, we found GNAS variants could not be detected in peripheral blood samples from CFD patients or their parents, and other potentially disease-causing gene variants related to CFD were not found.

Conclusions

For CFD patients with bone lesions involving the optic canal or sphenoid sinus regions, ocular symptoms should also be considered. Furthermore, we confirmed that CFD is not inherited, somatic variants in the GNAS gene are the main pathogenic gene causing CFD. Compared to the traditional methods in molecular genetic diagnosis of CFD, WES is more feasible and effective but limited in the type of samples.

Keywords:

• Craniofacial fibrous dysplasia
• vision disorders
• exome sequencing
• molecular diagnostic techniques
• Sanger sequencing

Acknowledgments

The authors are thankful to all the patients and their parents for their participation in the study, and the authors acknowledge American Journal Experts for editing this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are openly available in the NCBI repository at https://dataview.ncbi.nlm.nih.gov/object/PRJNA942503?reviewer=7em1rah0ethvhaah674dbat8rp. reference number (Bio project ID: PRJNA942503).

Additional information

Funding

This work was supported by the Eye Hospital of Wenzhou Medical University under Grant [No. ZYQNYS 201901].