Uncovering Low-Level Maternal Gonosomal Mosaicism in X-Linked Agammaglobulinemia: Implications for Genetic Counseling.

X-linked agammaglobulinemia (XLA) is a clinically and genetically well-defined immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent bacterial infections, profound hypogammaglobulinemia, and few or no circulating B cells. XLA is caused by mutations in the gene, which encodes Bruton's tyrosine kinase (BTK). Because of its X-linked recessive inheritance pattern, XLA virtually only affects males, and the mother is the carrier of the mutation in 80-85% of the males with this condition. In the remaining 15-20% of the cases, the affected male is considered to have a mutation. Here, we present the case of a child with a diagnosis of XLA caused by a missense mutation in the gene (c.494G>A/p.C165Y). Apparently, his mother was wild type for this gene, which implied that the mutation was , but careful analysis of Sanger electropherograms and the use of high-coverage massive parallel sequencing revealed low-level maternal gonosomal mosaicism. The mutation was detected in various samples from the mother (blood, urine, buccal swab, and vaginal swab) at a low frequency of 2-5%, and the status of the patient's mutation changed from to inherited. This study underscores the importance of accurately establishing the parents' status on detection of an apparently mutation in a patient, as inadvertent low-level mosaicism may lead to misinterpretation of the risk of recurrence, vital for genetic counseling.