| Part I Clinical diagnosis and molecular etiology of neurofibromatosis type 1Objective:Neurofibromatosis type 1（NF1）is an autosomal dominant disorder with equal sex incidence that is accompanied by abnormalities in multiple tissues derived from the neural crest with a prevalence of approximately 1 per 3,000.It is characterized by neurofibromas,cafe-au-lait macules,axillary freckling,optic pathway tumor,distinctive osseous lesion,and iris Lisch nodules.Inactivating variants in the NF1 gene have been identified to be correlated with NF1.This tumor suppressor gene is located at 17q11.2.This study is aimed at analyzing both the laboratory and radiographic information in these Chinese patients and understanding the NF1 gene pathogenic variants that occurred in these Chinese families.Methods:We obtained clinical data and peripheral blood samples.Ten families with NF1 were investigated in our study,and all were of the Chinese Han ethnicity but from different regions.Ten probands and eighteen relatives of these families were diagnosed with NF1 based on the diagnostic criteria established by the National Institutes of Health（NIH）.All of these probands mainly complained of osseous lesions.PCR was used to analyze and sequence the variants.We collected both laboratory and radiological information.Results:We detected five novel pathogenic mutations including two de novo variants in these ten families:one missense mutation,p.Cys709Arg（c.2125T>C）,in exon 18 and four frameshift mutations:p.Leu1459Profs*2（c.4436dupT）in exon 34;p.Lys99Argfs*4（c.296de1A）in exon 4;p.Leu762Cysfs*2（c.2283de1A）in exon 19;and p.Leu1522Ilefs*53（c.45624563dupAT）in exon 34.Conclusion:Novel pathogenic mutations in the NF1 gene in these families correlated with the phenotype and genotype and explained the clinical manifestations of these patients.The results help us to understand the genetic basis of patients with neurofibromatosis type 1 in China.Our study expands the pathogenic variant spectrum of the NF1 gene and may be helpful in genetic counseling and prenatal genetic diagnosis.Part II Clinical diagnosis and molecular etiology of X-linked hypophosphatemiaObjective:X-linked hypophosphatemia（XLH）is the most frequent form of hereditary hypophosphatemia.XLH caused principally by inactivating mutations of PHEX gene is a X-linked dominant disorder that is characterized by hypophosphatemia and defects in bone mineralization such as rickets and osteomalacia.This study is aimed to elucidate genetic characteristics and describe clinical features in six different Chinese families with X-linked dominant hypophosphatemia.Methods:We obtained clinical data and peripheral blood samples.We investigated the clinical characteristics and PHEX gene mutation analysis of six unrelated Chinese families with XLH in the present study.All 22 exons of PHEX gene,including the exon-intron boundaries,were amplified and then directly sequenced.We collected both laboratory and radiological information.Results:The sequence analysis of PHEX gene revealed four novel mutations including four de novo mutations in these six families.We detected four novel pathogenic variants in these ten families:two missense mutations,p.Pro671 Thr（c.2011C>A）),in exon 20;p.Met271Arg（c.812T>G）,in exon 7,one deletion mutation,p.Ala135ProfsX9（c.402delA）,and one splicing mutation,c.1174-3C>GConclusions:The molecular diagnosis of PHEX gene mutations in these families correlated with the phenotype and genotype and explained the clinical manifestations of these patients.The results help us to understand the genetic basis of patients with XLH in China.Our study expands the mutation spectrum of the PHEX gene and may be helpful in conducting genetic counseling and facilitating prenatal genetic diagnosis. |
