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Multi‐gene panel testing improves diagnosis and management of patients with hereditary anemias
Author(s) -
Russo Roberta,
Andolfo Immacolata,
Manna Francesco,
Gambale Antonella,
Marra Roberta,
Rosato Barbara Eleni,
Caforio Paola,
Pinto Valeria,
Pignataro Piero,
Radhakrishnan Kottayam,
Unal Sule,
Tomaiuolo Giovanna,
Forni Gian Luca,
Iolascon Achille
Publication year - 2018
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.25058
Subject(s) - medicine , anemia , diamond–blackfan anemia , hereditary spherocytosis , proband , hemolytic anemia , compound heterozygosity , spherocytosis , mutation , pediatrics , gene , genetics , biology , ribosome , splenectomy , rna , spleen
Mutations in more than 70 genes cause hereditary anemias (HA), a highly heterogeneous group of rare/low frequency disorders in which we included: hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA) and Diamond‐Blackfan anemia; hemolytic anemias due to erythrocyte membrane defects, as hereditary spherocytosis and stomatocytosis; hemolytic anemias due to enzymatic defects. The study describes the diagnostic workflow for HA, based on the development of two consecutive versions of a targeted‐NGS panel, including 34 and 71 genes, respectively. Seventy‐four probands from 62 unrelated families were investigated. Our study includes the most comprehensive gene set for these anemias and the largest cohort of patients described so far. We obtained an overall diagnostic yield of 64.9%. Despite 54.2% of cases showed conclusive diagnosis fitting well to the clinical suspicion, the multi‐gene analysis modified the original clinical diagnosis in 45.8% of patients (nonmatched phenotype‐genotype). Of note, 81.8% of nonmatched patients were clinically suspected to suffer from CDA. Particularly, 45.5% of the probands originally classified as CDA exhibited a conclusive diagnosis of chronic anemia due to enzymatic defects, mainly due to mutations in PKLR gene. Interestingly, we also identified a syndromic CDA patient with mild anemia and epilepsy, showing a homozygous mutation in CAD gene, recently associated to early infantile epileptic encephalopathy‐50 and CDA‐like anemia. Finally, we described a patient showing marked iron overload due to the coinheritance of PIEZO1 and SEC23B mutations, demonstrating that the multi‐gene approach is valuable not only for achieving a correct and definitive diagnosis, but also for guiding treatment.