The dilemma of X-linked agammaglobulinemia carriers

Abstract

Background: Many patients with X-linked agammaglobulinemia (XLA) nowadays have reached adulthood, as well as their sisters, possibly carriers of a deleterious Bruton tyrosine kinase variant. Studies on motherhood outcomes in families with XLA are lacking.

Objective: We sought to investigate adherence to carrier status screening, interest in preconception and prenatal genetic counseling, and reproductive decisions in relatives with XLA.

Methods: In this multicenter, retrospective cohort study, we collected a 3-generation pedigree and data on mothers and sisters of patients with XLA, including carrier status and pregnancy outcome.

Results: Data on 53 adults with XLA, 52 mothers, and 33 sisters were collected. All XLA sisters received genetic counseling. Forty percent of the sisters chose to undergo carrier status determination, and 60% of them chose invasive prenatal testing. The main reasons for the sisters to decide not to undergo genetic testing were their young age and the willingness to carry on with the pregnancy regardless of the outcome of the genetic test, followed by the willingness to postpone the decision at the time of pregnancy and the decision to not have children. Prenatal testing resulted in 5 XLA diagnoses, with 2 pregnancy terminations, 1 miscarriage, and 2 XLA live births. Three carriers refused prenatal testing and had 6 live births, including 3 XLA-affected sons. One sister was diagnosed as a carrier after the birth of an XLA-affected son. In total, 9 XLA diagnoses were made, including 6 live births.

Conclusions: A number of XLA sister carriers decided to carry on with their pregnancy after receiving the diagnosis of an affected fetus or after refusing prenatal testing. We propose to initiate a more extensive collaborative study to verify the effect of genetic counseling on families with XLA in other cohorts from different countries.

Keywords: Bruton; X-linked agammaglobulinemia; XLA; carrier; genetic counseling; genetic diagnosis; inborn errors of immunity; pregnancies; prenatal testing.

Fig 1

Reproductive outcomes of the family members of patients with XLA, who are represented by red shapes. Female patients carrying a pathogenic BTK variant (carriers) are represented by red/gray shapes; female and male patients carrying wild-type (WT) BTK variants are represented by pink and blue shapes, respectively.