BLK

Inheritance Pattern: Unknown

Disease ID:MONDO:0013242

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013242

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: ClinGen

*BLK*: monogenic diabetes, autosomal dominant (MONDO: 0015967) Refuted *BLK* was first reported in relation to autosomal dominant monogenic diabetes in 2009 (Borowiec et al., PMID: 19667185). Evidence describing this gene-disease relationship includes case-level data (1.1 points), segregation data (0.5 points), case-control data (0 points), and experimental data (1 point). Summary of case-level and experimental data: 2.6 points. Variants in this gene have been reported in at least 6 probands in 3 publications (PMIDs: 19667185, 28095440, 31638168). Variants segregated with disease in 22 additional family members in the initial report (PMID: 19667185). Importantly, the families in the paper were selected for prior linkage to the 8q23 region that contains BLK. While a total of 723 kb in this region was sequenced in these families, attribution of the variant-disease segregation to linkage with an untyped variant in another gene cannot be ruled out and seems particularly likely in the family segregating variants too common for the disease, including p.Ala71Thr (rs55758736) described in the proceeding paragraph. In 2 probands in a later publication (PMID 31638168), the BLK variants were unlikely to be causal because there was an alternate and more likely molecular cause. The *BLK* variant p.Ala71Thr, the first coding variant to be implicated in MODY (PMID: 19667185), was studied in three large type 2 diabetes (T2D) case-control cohorts and while found to be nominally associated with the polygenic disease T2D (OR = 1.47, p = 0.035) in 4,901 T2D cases and 4,280 controls, especially in the setting of obesity (OR = 2.44, p = 0.004), was found in 52 normoglycemic controls, providing strong evidence against being causal for monogenic diabetes (PMID 23224494). In addition, the p. Ala71Thr variant has a high allele frequency in gnomAD 2.1 (e.g., MAF = 0.012 in European non-Finnish and 0.04 in Africans), much higher than expected for MODY. The p.Ala71Thr variant was not associated with T2D in the AMP T2D Knowledge Portal (type2diabetesgenetics.org), though a common (MAF = 0.50) intronic BLK variant was modestly but GWAS significantly associated with T2D in the DIAMANTE Study (OR = 1.04, p = 6 x 10-10) in the Portal. The four noncoding variants reported by Borowiec et al. have allele counts ranging from 0 to 2 in gnomAD. The noncoding variants were associated with a 60-80% reduction in luciferase expression, and the Ala71Thr variant abolished expression of Pdx1 and Nkx6.1 in MIN6 mouse insulinoma cells (PMID:19667185). Laver et al (PMID: 35108381) reported a lack of enrichment of ultra-rare (MAF<6X10-6) protein-truncating and missense variants in *BLK*, *PAX4*, and *KLF11* in a large cohort of cases with suspected MODY (n=1227) compared to population cohort (UK Biobank =185,898), gnomADv2 and gnomADv3. They also showed a similar lack of enrichment of any protein-truncating variants in *BLK*, *PAX4*, and *KLF11* in the MODY cohort. While there is evidence for a gene-disease association between *BLK* and diabetes in the form of expression studies and in vitro functional assays, very little convincing case-level evidence for involvement in monogenic diabetes has accumulated since BLK was first proposed as a MODY gene. Moreover, some of the originally implicated variants have proven to be too common in the general population and normoglycemic individuals to be implicated in monogenic diabetes. Finally, the high prevalence of BLK LoF variants in the general population and lack of over-representation of rare *BLK* variants in a monogenic diabetes cohort argue strongly against a causal role of *BLK* in monogenic diabetes. In summary, there is limited evidence to support this gene-disease relationship. There appears to be strong evidence to contradict the *BLK*-monogenic diabetes gene-disease relationship that warrants refuting the association (originally asserted as maturity-onset diabetes of the young 11, MODY11, MIM: 613375). As described above, *BLK* variants may play a role in polygenic type 2 diabetes (MIM: 125853); this relationship will not be curated at this time since the contribution would be in the form of common variants with a small effect. In addition to its proposed role in monogenic and type 2 diabetes, *BLK* has been proposed as a possible causal gene in antibody deficiency. The *BLK* (B lymphocyte kinase) gene encodes a Src family tyrosine kinase, which plays a role in B cell receptor signaling (BCR) and B cell development. A rare heterozygous missense variant in *BLK*, p.Leu3Pro has been reported in 2015 in 2 related common variable immunodeficiency (CVID) patients, but not other healthy family members (Compeer et al, PMID: 25926555). The index patient had a history of severe recurrent pulmonary infections from infancy and further evaluation demonstrated hypogammaglobulinemia (low IgG, IgA, close to normal IgM) and impaired vaccine antibody responses. The patient had a small reduction in peripheral B cells and IgG switched memory B cells were low normal, but IgA and IgM-memory B cells were significantly decreased. The patient had no autoimmunity or lymphoproliferation. The patient’s father who had the variant was also symptomatic. Functional studies were performed with transformed B cell lines overexpressing the mutant, which suggested a functional impact of this variant in terms of BCR-mediated antigen presentation to antigen-specific T cells, and alteration in BCR endosomal routing on antigen binding. The variant-expressing cell line also showed reduction in the ability to transmit tonic and ligand-induced BCR signals (PMID: 25926555). In mouse models it has been shown that Blk is not essential for murine B cell development and activation (Texeido G et al, 2000PMID: 10648608,). Therefore, the association between *BLK* gene variants and an antibody deficiency is limited, at best, and requires further patients as well as functional studies for a definitive correlation.

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0015517

Submitter: PanelApp Australia