Bruton-type agammaglobulinemia, or X-linked agammaglobulinemia (XLA) was the first immunodeficiency to be described (Burton,1952). The relationship of BTK to XLA was first reported in 1993 (PMIDs: 8425221, 8380905). Btk is a tyrosine kinase, which is critical in the maturation of Pre-B cells to mature B cells. The absence of functional Btk leads to failure of B-cell development that incapacitates antibody production in XLA patients leading to recurrent bacterial infections (reviewed in PMID: 26909497). Over 900 unique variants have been reported in humans (BTKbase; PMID: 16969761), including missense, nonsense, frameshift, splicing, small indels, and gross insertions or deletions. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Twenty-three unique variants from 23 probands in 4 publications were curated (PMIDs: 8380905, 17765309, 7880320, 8162056). Variants in this gene segregated with disease in 8 additional family members (PMIDs: 17765309, 8162056). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. Experimentally, this gene-disease relationship is supported by its role as a tyrosine kinase in B-cell development (PMID: 11606584) and its expression in relevant cells and tissues (PMID: 8380905), both of which are altered in patient cells (PMID: 8425221). Further support is provided by chimeric mice (PMID: 7552995), the xid mouse model (PMID: 8332900), and a null mouse model (PMID: 7552994), all of which recapitulate features of XLA. In summary BTK is definitively associated with x-linked Bruton-type agammaglobulinemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Of note, this gene has also been implicated in isolated growth hormone deficiency type III (MONDO:0010615). This has been assessed separately given the lack of known overlapping molecular mechanism and distinct phenotype. Furthermore, somatic variants in BTK are associated with malignancy, which is not considered here.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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