The relationship between BLNK and Agammaglobulinemia 4, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of February, 2021. BLNK encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. Agammaglobulinemia is characterized by absence of circulating B cells and low or absent serum immunoglobulin levels (PMID: 10583958). BLNK was first reported in relation to autosomal recessive Agammaglobulinemia 4 in 1999 (Minegishi et al, PMID: 10583958). Variants reported in this gene thus far include missense, nonsense, frameshift and splice site variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (7.5 points): There have been 8 patients, including a sibling pair, from 6 publications, till date, reported with biallelic variants in BLNK (PMID: 10583958, 24582315, 30619340, 25893637, 32194234, 19302039). The mechanism of disease is expected to be biallelic loss of function.
Summary of experimental data (4.5 points): This gene-disease association is supported by in-vitro functional assays and animal models. BLNK is expressed in B lymphocytes (PMID: 10583957). BLNK is involved in BCR activation and B cell differentiation (PMID: 9697839). BLNK defects lead to a block of B-cell differentiation from the pro-B cell to the pre-B cell stage and accumulation of immature B cells (PMID: 24582315). A targeted knock-out mouse model (PMID: 10583957) has been reported that recapitulates the B-cell defect.
In summary, the evidence to support the gene-disease relationship of BLNK and Agammaglobulinemia 4 is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Antibody Immunodeficiency GCEP on March 16, 2021 (SOP Version 8).
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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