Clinic And Genetic Characteristics Of 46,XY Sex Reversals In A Line With NROB1 Duplication

Background46,XY sex reversal syndrome is a rare genetic disorder of sexual dysplasia,and the estimated incidence is about 1/100,000.NR0B1 gene duplication on Xp21 is an uncommon molecular genetic etiology,By searching the websites of Pubmed,CNKI and Wan Fang,only 18 patients have been reported.Their clinical features including gonadal dysplasia,with or without mental retardation,growth retardation,etc.The pathogenesis is currently unclear.There were few research on clinical and genetic characteristics of 46,XY sex reversal caused by NROB1 gene duplication.The number is even fewer of carries with normal 46,XX female phenotype.Research on proband and her family in our hospital has great clinical and theoretical significance.PurposeTo investigate the clinic and genetic characteristics of a family with 46,XY sex reversal syndrome caused by NR0B1 gene duplication on Xp21.Methods1.Collected clinical data of a 46,XY female and some of her family member who admitted to our hospital in June 2017.2.Family investigation was conducted on 46,XY women and 46,XX carriers in this family line.3.2-3ml peripheral blood of her family members were collected for sex hormone detection and sex chromosome(FISH)detection.4.High-throughput sequencing(CNV-Seq)and whole gene sequencing were performed on 46,XY females and 46,XX female carriers in the family lines.5.46 and XX female carriers from the family members were retained for X chromosome inactivation study.Results1..Four generations members of proband were investugated.Both the proband and her sister were diagnosed 46,XY sex reversal syndrome.The NR0B1 gene duplication inherited from her mother.Her mother and her maternal grandmother’s siblings had normal gestation history,and had never experienced infertility,and had no special clinical manifestations such as mental retardation and special facial features.There is no history of germ cell tumors in women in the family.2.The sex hormone levels of FSH and LH in both sisters were increased,and the increase in the elder sister was more obvious,suggesting hypertrophic gonadotrophic dysplasia.The sex hormone levels of her mother were normal.3.According to the gonadal ultrasound and MRI examination,the proband girl had no testis.Despite she had uterus,but no ovaries or dysplastic ovaries were found,while her sister had uterus and ovaries.4.Both sisters’ chromosome karyotype was 46,XY,SRY gene positive.CNV-Seq indicated the NROB1 and MAGEB gene duplication in Xp21.2 was inherited from mother.5.X chromosome inactivation test found 79% of X chromosome inactivation in the proband’s mother,indicating a moderate inactivation deviation,suggesting X chromosome inactivation was biased.Conclusion1.Carrying NROB1 gene duplication is the cause of 46,XY sex reversal in this family;46.There is preferential inactivation of X chromosome in 46,XX female carriers,which may be one of the reasons for the normal clinical characteristics of 46,XX female carriers.2.According to the clinical investigation of this family,both the proband and her sister were the patients,and their mother was the carrier,suggesting that the NROB1 duplication carried by the proband’s mother in this family may be spontaneous variation.The proband and her sister carrying the same gene duplication,and other differences in clinical phenotypes suggest that there may be a more complex regulatory mechanism.