BTK was first reported in relation to x-linked isolated growth hormone deficiency type III in 1994 (Conley ME, et al., 1994, PMID: 7849697; Duriez B, et al., 1994, PMID: 8013627 ). Isolated growth hormone deficiency type III is characterized by agammaglobulinemia and markedly reduced numbers of B cells, short stature, delayed bone age, and good response to treatment with growth hormone (Conley ME, et al., 1991, PMID: 1880652). The disease was originally described by Fleisher et al., 1980 (PMID: 7189577), however no association with BTK was made in those patients or the subsequent patient described by Monafo et al., 1991 (PMID: 1872183). Furthermore, Stewart et al. (2008) provided an update on the family initially described by Fleisher et al. (1980), finding normal expression and autokinase activity. As such BTK was not considered to be causative of the X-linked hypogammaglobulinemia and isolated growth hormone deficiency observed in this family and an alternate candidate gene, ELF4, was identified with a single Ser369Pro missense variant identified segregating with disease. In BTK, three unique variants (one missense, one nonsense, and one intronic) have been identified in three male probands in two publications (PMIDs: 7849697 and 8013627). This gene-disease association is supported by experimental evidence consistent with the agammaglobulinemia observed in these patients including the role of BTK as a tyrosine kinase in B-cell development (PMID: 11606584) and its expression in relevant cells and tissues (PMID: 8380905), as well as chimeric mice (PMID: 7552995), the xid mouse model (PMID: 8332900), and a null mouse model (PMID: 7552994), all of which recapitulate features of XLA. However, no experimental evidence supporting a relationship with the isolated growth hormone deficiency has been reported and no convincing genetic evidence has emerged relating BTK to the isolated growth hormone deficiency since it was last reported in 1994. In summary, the evidence supporting the relationship between BTK and x-linked isolated growth hormone deficiency type III has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role BTK plays in this disease. Of note, this gene has also been implicated in Bruton-type agammaglobulinemia (MONDO:0010421), which has been assessed separately.
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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