Abstract:

Objective

To investigate the clinical phenotypic characteristics，pathogenic genes and mutation sites of patients with neurofibromatosis typeⅠ（NF1）in a family.

Methods

The clinical and genetic data of two families with clinical diagnosis of NF1 were collected，including the patient and relatives who participated in the study were asked for medical history and detailed ophthalmic examination.Deoxyribonucleic acid（DNA）was extracted from peripheral venous blood of patients and some family members.The pathogenic genes and mutation sites were screened by whole exon capture sequencing（WES）.The degree of conservation in species was evaluated by using ugene software，and the harmfulness of mutation was evaluated by using polyphen 2 and mutation taster software.Sanger sequencing was used for family co separation verification，and different treatment schemes were given according to the clinical phenotype andpathogenesis characteristics.

Results

Family 1 included 2 patients and 3 normal family members.Family 2 contains one patient and one normal family member.After ophthalmic examination，the proband of family 1 and family 2 were found to have coffee milk spots，iris Lisch nodules and orbital periorbital plexiform neurofibroma（oppn）.Sequencing data showed that the NF1 gene was the pathogenic gene of patients in two families，and pathogenic mutations were detected in the NF1 gene.A heterozygous frameshift mutation of c.7240-7241delAG（p.Ser2414Argfs*12）was found in the NF1 gene of the proband of family 1（f1-Ш 1）and his sick brother（f1-Ш 2）.A c.2570del（p.Asn857llefs*21）heterozygous frameshift mutation was found in the NF1 gene of the proband of family 2（F2-Ш 1）.The results of Ugene software showed that the two mutations were highly conserved in many species，and the results of polyphen 2 and mutation taster software showed that the two mutations were highly pathogenic.In combination with the condition of proband 1 and full communication with his family members，the patient was not given special treatment for the time being，and only the patient was followed up for a long time.The appearance of proband 2 was significantly improved after surgical treatment，and the tumor did not recur six months later.

Conclusions

NF1 gene mutation is the main cause of type I neurofibromatosis.The disease caused by NF1 gene mutation has typical genetic heterogeneity and clinical heterogeneity.Different mutations will lead to different clinical phenotypes of patients.The diversity of disease phenotypes needs to provide individualized treatment for patients.In this study，heterozygous frameshift mutations in NF1 gene were detected in both families by full exon sequencing；Among them，c.2570del（p.Asn857llefs*21）was reported for the first time and further confirmed the clinical diagnosis at the gene level.At the same time，this research method can also provide reference for prenatal diagnosis，genetic counseling and analysis of the correlation between genotype and phenotype of the two families in the future.

Key words: Neurofibromatosis type 1, Shift code mutation, Sanger sequencing, Wholeexome sequencing