Abstract:

Objective To identify the genetic etiology of a family with abnormal genital abnormal fetal genitalia in two pregnancies and to provide reference for effective genetic counseling. Methods After karyotype analysis，ultrasound examination and autopsy of cord blood were used to make a preliminary diagnosis，CYP21A2 gene mutation was detected in the fetus and family members，and the source of mutation was verified. Results The karyotype of blood chromosome was 46，XX，inv（9）（p11q13）. Ultrasonography showed abnormal fetal genitalia and adrenal enlargement. The results of autopsy were consistent with those of ultrasound examination，and the pathological examination showed the adrenal cortex of the fetus was microcapsule hyperplasia. Restriction fragment length polymorphism analysis of PCR⁃amplified fragments for the CYP21A2 gene showed the fetus had a large homozygous deletion（~30 kb），and both parents were carriers. We also identified 11 homozygous CYP21A2 gene variants in the fetus，including c.92C > T（p.P31L），c.293⁃13C > G，c.332_339del8（p.G111Vfs*21），c.518T > A （p.I173N），c.710T > A（p.I237N），c.713T > A（p.V238E），c.719T > A（p.M240K），c.844G > T（p.V282L）， c.923dupT（p.L308Ffs*6）、c.955C > T（p.Q319*）and c.1069C > T（p.R357W），which were inherited from both parents. These homozygous variants indicated the formation of CYP21A1P/CYP21A2 chimeric gene due to the 30 kb homozygous deletion，resulting in inactivated of the CYP21A2 gene. Conclusions The mutation of CYP21A2 gene is the cause of 21⁃hydroxylase deficiency，which caused the fetus with external genital malformation in two pregnancies in this family. The combination of cord blood chromosome karyotype analysis，prenatal ultrasound and autopsy verification，and appropriate genetic testing programs clarified the cause of the genetics，providing an important basis for genetic counseling and prenatal diagnosis of the family.

Key words:

genital anomalies, adrenocortical hyperplasia, prenatal diagnosis, karyotype analysis, CYP21A2 gene