Aberrant splicing caused by a homozygous AK2 c.498 + 1G > A variant in a patient with reticular dysgenesis and concurrent B-cell acute lymphoblastic leukemia.
Longkai He, Chunyan Zhao, Peng Lu et al.
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Case in brief
A boy with reticular dysgenesis (RD), a severe immunodeficiency associated with biallelic AK2 loss of function, was also diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). Genetic testing identified a homozygous AK2 c.498 + 1G > A splice-site variant. A minigene assay showed disruption of the canonical 5′ splice donor, producing an aberrant transcript with a 4-bp intronic insertion after exon 5, a frameshift and premature termination codon. The variant was classified as pathogenic. The authors concluded that it causes loss of AK2 function; the clinical significance of the leukemia occurring alongside RD remains uncertain.
What made this case unusual
The reported coexistence of RD and B-ALL in a patient with an AK2 variant was not previously reported in association with an AK2 variant, according to the authors; its significance requires further investigation.
Diagnostic / clinical pearl
For a suspected pathogenic splice-site variant, functional splicing analysis can demonstrate the resulting transcript abnormality and support its predicted loss-of-function effect.