Submission Details

PKLR was first reported in relation to autosomal recessive pyruvate kinase deficiency (PKD)/anemia in 1991 (Kanno et al., PMID: 1896471). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found distinct differences in molecular mechanism, inheritance pattern, and phenotype. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive pyruvate kinase deficiency and autosomal dominant pyruvate kinase hyperactivity. Due to very limited evidence, a curation for autosomal dominant pyruvate kinase hyperactivity was deemed unnecessary. At least 19 variants (missense, in-frame deletion, splicing, and nonsense) that have been reported in more than 20 probands in 4 publications are included in this curation (PMID: 1896471, 9057665, 9827908, 16704447). While a wide array of mutations are linked to disease, there are three recurrent mutations seen in affected patients (two missense and one nonsense). This gene-disease relationship is also supported by experimental evidence (expression, functional alteration, and a mouse model; PMID: 1896471, 17466543, 11960989). Prenatal anemia can present with hydrops fetalis or fetal demise. Confirmation of anemia and PKD deficiency is possible via umbilical blood vessel sampling and amniocentesis. Neonatal diagnosis of jaundice/anemia is also possible. The mechanism of pathogenicity is reported to be loss-of-function. In summary, there is definitive evidence supporting the relationship between PKLR and autosomal recessive PKD. 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 Prenatal GCEP on the meeting date 2/07/2024 (SOP Version 10).