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SRP72-Associated Bone Marrow Failure Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Among inherited BMFS, amegakaryocytic thrombocytopenia, Fanconi anemia, dyskeratosis congenita, Shwachman−Diamond syndrome, congenital amegakaryocytic thrombocytopenia, Blackfan−Diamond anemia, reticular dysgenesis, Pearson syndrome, severe congenital neutropenia, and thrombocytopenia absent radii are relatively common and well known. However, there are a few BMFS that have caught our attention only in recent years after identification of the culprit genes (e.g., SRP72 on chromosome 4q12, ERCC6L2 on chromosome 9q22.32, and DNAJC21 on chromosome 5p13.2) [1–4].
Hereditary red blood cell membrane defects. Detection of PIEZO1 mutations associated with SPTA1 mutations. An unusual clinical case of hereditary xerocytosis
Published in Pediatric Hematology and Oncology, 2020
Carmelo Fortugno, Eulalia Galea, Renato Cantaffa, Francesco Gigliotti, Rachele Lucia Fabiano, Valentina Talarico, Giuseppe Raiola, Maria Concetta Galati
At the age of two, the search for genetic variants in the coding regions of the causative genes of hereditary hemolytic anemias was performed on the patient's DNA by means of targeted-Next Generation Sequencing (t-NGS) analysis of a multi-gene panel including 86 genes involved in RBC membrane defects, congenital dyserythropoietic anemias, Blackfan-Diamond anemia, hemolytic anemias due to enzyme deficiencies, sideroblastic anemia, microcytic anemias and erythrocytosis.10 The filtering of the gene variants was carried out using a dedicated pipeline and considering possible variants of the genes associated with the phenotype. This pipeline has considered non-synonymous exonic variants, in splicing or intronic site, not noted in public databases or noted with minor allele frequency (MAF) lower than 0.01 in the general population. The data obtained by t-NGS was confirmed on the patient's DNA by amplification with specially designed primers and subsequent Sanger sequencing. The molecular analysis performed on the patient's DNA revealed the presence of numerous variants, some with unknown pathogenetic significance. The variants considered to be of relative clinical importance are: 1) Missense mutation in heterozygous c.7558A > G, p.Lys2520Glu in the PIEZO1 gene, described as causative of Hereditary xerocytosis (SIFT score 0.00, damaging; PolyPhen2 score 0.158, benign). 2) Missense heterozygous mutation c.5029G > A, p.Gly1677Arg in the SPTA1 gene, causative of Hereditary spherocytosis in the autosomal recessive form (SIFT score 0.32, tolerated; PolyPhen2 score 0.935, possibly damaging). 3) Intronic variant in heterozygous c.6531-12C > T in the SPTA1 gene. This variant is noted in the HGMD database (CS995155) as a common functional polymorphism which determines a reduced expression of α-spectrin (αLELY). This mutation is usually found associated with the α1857 Leu-Val mutation in exon 40, but not in our case.11,12 This is not a pathogenetic mutation per se, but if associated in trans with another mutation affecting the same gene, it could contribute to determine a picture of Hereditary spherocytosis (Table 3).