TY - JOUR
T1 - Genotype-Phenotype Correlation and Molecular Heterogeneity in Pyruvate Kinase Deficiency
AU - Bianchi, Paola
AU - Fermo, Elisa
AU - Lezon-Geyda, Kimberly
AU - van Beers, Eduard
AU - Morton, D Holmes
AU - Barcellini, Wilma
AU - Glader, Bertil
AU - Chonat, Satheesh
AU - Ravindranath, Yaddanapudi
AU - Newburger, Peter
AU - Kollmar, Nina
AU - Despotovic, Jenny
AU - Verhovsek, Madeleine
AU - Sharma, Mukta
AU - Kwiatkowski, Janet L
AU - Kuo, Kevin H M
AU - Wlodarski, Marcin
AU - Yaish, Hassan
AU - Holzhauer, Susanne
AU - Wang, Heng
AU - Kunz, Joachim
AU - Addonizio, Kathryn
AU - Al-Sayegh, Hasan
AU - London, Wendy
AU - Andres, Oliver
AU - van Wijk, Richard
AU - Gallagher, Patrick G
AU - Grace, Rachael
N1 - Funding Information:
RFG, PB, WB, BG, EJvB, KK, JLK, SC have served as scientific advisors Agios Pharmaceuticals. RFG, BG, EJvB, WB received research funding from Agios Pharmaceuticals. The remaining authors declare no competing financial interests.
Funding Information:
The authors would like to acknowledge all the patients with pyruvate kinase deficiency who contributed to this Natural History Study data. The study was supported by Fondazione IRCCS Ca' Granda Policlinico Milano, Project number RC 175/04, 2015‐2017. The Pyruvate Kinase Deficiency Natural History Study was supported by research funding from Agios Pharmaceuticals.
Publisher Copyright:
© 2020 Wiley Periodicals, Inc.
PY - 2020/5
Y1 - 2020/5
N2 - Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.
AB - Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.
KW - Adolescent
KW - Adult
KW - Anemia, Hemolytic, Congenital Nonspherocytic/genetics
KW - Child
KW - Child, Preschool
KW - Female
KW - Genetic Association Studies/methods
KW - Humans
KW - Infant
KW - Infant, Newborn
KW - Male
KW - Middle Aged
KW - Pyruvate Kinase/deficiency
KW - Pyruvate Metabolism, Inborn Errors/genetics
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85080922382&partnerID=8YFLogxK
U2 - 10.1002/ajh.25753
DO - 10.1002/ajh.25753
M3 - Article
C2 - 32043619
SN - 0361-8609
VL - 95
SP - 472
EP - 482
JO - American Journal of Hematology
JF - American Journal of Hematology
IS - 5
ER -