BLK – Monogenic Diabetes

BLK encodes B lymphocyte kinase, a candidate gene for maturity-onset diabetes of the young (MODY). In a cohort of 60 Russian children with non–type 1 diabetes mellitus, whole-exome sequencing identified BLK variants in 2 probands (one with a compound GCK+BLK genotype and one with GCK+BLK+WFS1) among 33 patients with causal variants ([PMID:31638168]). No independent BLK mutations were reported in adult MODY cases using targeted NGS panels. Overall, genetic evidence is limited: only 2 unrelated probands carry BLK variants, and no familial segregation has been documented.

Functional reappraisal of the BLK p.Ala71Thr variant (c.211G>A (p.Ala71Thr)) revealed its presence in 52 normoglycaemic individuals and absence in MODY families, arguing against a highly penetrant role in monogenic diabetes ([PMID:23224494]). No in vivo or rescue studies support BLK pathogenicity in β-cell dysfunction. Collectively, the data provide limited genetic support and disputed functional evidence for BLK’s involvement in monogenic diabetes. Key take-home: current evidence does not support routine BLK testing for MODY diagnostics.

References

• Molecular Medicine Reports • 2019 • Whole-exome sequencing in Russian children with non-type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY-related and unrelated PMID:31638168
• Diabetologia • 2013 • Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes PMID:23224494

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