No abstract

ABSTRACT. We investigated the feasibility of interleukin-2 receptor gamma (IL2Rg) gene based on gene mutation analysis and prenatal diagnosis of X-linked severe combined immunodeficiency (X-SCID). Blood samples of patients and their parents of X-SCID (family 1) and X-SCID (family 2) were collected. IL2Rg gene sequences of the 2 families were analyzed using bi-directional direct sequencing by polymerase chain reaction. DNA sequence changes in the IL2Rg gene exon region and shear zone were also analyzed. We also sequenced the IL2Rg gene in 100 healthy individuals. Prenatal genetic diagnoses for a high-risk fetus in family 1 were performed by chorionic villus sampling after determining each family's genotypes. The suspect female in family 1 underwent carrier detection. Two novel mutations of IL2Rg gene were identified, including c.361-363delGAG (p.E121del) in the patient and his mother in family 1, and c.510-511insGAACT (p.W173X) heterozygous mutation in the proband's mother in family 2. These mutations were absent in the 100 controls. Prenatal diagnosis IL2Rg gene novel mutation of early pregnancy in the female fetus of family 1 was performed; the fetus was heterozygous, which was confirmed at postnatal follow-up. The suspect female in family 1 showed no mutation in carrier detection. The novel p.E121del and p.W173X mutations in IL2Rg may have been the primary causes of disease in 2 families with X-SCID. In couples with an X-SCID reproductive history, prenatal gene mutation analysis of IL2Rg can effectively prevent the birth of children with X-SCID and carrier detection for suspected females.

What are the novel findings of this work?Trio-based prenatal exome sequencing (pES) had an incremental yield of 31% in ongoing pregnancies with fetal ultrasound anomalies but undiagnosed by copy-number variant sequencing (CNV-seq). Comprehensive analysis of nuclear exome coding and splicing regions, as well as mitochondrial genome, provided not only diagnostic findings but also incidental findings (in 7.8% cases) that were important for affected families. What are the clinical implications of this work?Trio-based pES is an efficient diagnostic method for families with fetal ultrasound anomalies and normal CNV-seq results. The incidental findings and parental carrier status detected by trio-based pES extend its clinical application, but careful genetic counseling is warranted.