Update on the genetic landscape of Diamond‐Blackfan anemia in the Russian Federation

Citations Over Time

Abstract

To the Editor Diamond-Blackfan anemia (DBA) is a rare clinically and genetically heterogeneous congenital bone marrow failure syndrome. The cohort of 187 patients from 179 families diagnosed with DBA was recruited during the period 1993 to 2019 in Russia. Here we report the update on the genetic landscape of DBA in Russia since 2015, when our previous paper was published describing 77 probands,1 so the increment in patients since the 2015 manuscript is 110 individuals from 102 families. Of 110 individuals (2015-2019 period), blood samples were available for 98 patients from 92 families. For the details of molecular genetic testing, see Supporting Information. In the total cohort of 187 patients, the female:male ratio was 1. In 105 patients (56.1%), the clinical diagnosis was established before the age of 3 months, in 34 patients (18.2%) it was established between 3 and 12 months of age, and in the remaining patients, it was established after 1 year of age. Eighty-six patients received glucocorticoid therapy: 51 responded completely or partially, and 35 experienced treatment failure. Nine patients spontaneously went into complete or partial remission during their disease. The frequency of congenital malformations is 40.2%, which is much lower than in the Czech and Greek registries,2, 3 but is in line with the data published by other authors.4-6 The most common anomalies were craniofacial dysmorphism, heart malformations, short stature, and short neck. In our previous paper1 35 rare RP genes variants in 57 DBA probands were identified. The application of NGS and MLPA methods in the remaining 22 probands allowed us to find 7 additional genetic variants. Among them three previously described variants9-11 (c.2T > C/ p.Met1Thr in GATA1, c.384_385delAA/p.Asp130SerfsTer23 in RPS19 and c.357T > G/ p.Tyr119* in RPL11), three previously described gross deletions12-14 (Ex 1-3 deletion in RPS19, and whole gene deletions in RPL11 and RPL35a), and one novel variant in RPS29 (c.89T > C, p.Leu30Pro) were found. Of 98 patients (2015-2019 period), the diagnosis of DBA was confirmed in 74 cases from 68 families, including 34 previously undescribed variants in RP genes and 2 novel genetic changes—one in ADA2 and one in TSR2 genes (see Table 1). We also found five previously described gross deletions12-14 (whole gene deletions for RPL5, RPS17, RPS26, RPS35a, and deletion of one to three exons in RPS19). So, to date, 89 different heterozygous mutations in 11 different RP genes have been identified in 104 probands. Three individuals were found to carry variants in one of the following genes: ADA2, GATA1, and TSR2. In line with the data in previous reports,7, 8 most mutations are loss-of-function (LoF) variants and are located in the RPS19 gene (40 probands), followed by the RPL5 gene (18 probands). It is worth mentioning that the third most frequently mutated gene is RPS7 (eight probands). Previously known genetic changes (57 variants) have been revealed in 69 probands in the following genes: RPS19, RPL5, RPL11, RPS7, RPS26, RPS10, RPL35a, RPS24, and GATA1. Most of those variants were found in the RPS19 gene (one balanced translocation detected in another study by means of standard karyotyping, one whole gene deletion, seven frameshift, five nonsense, five missense, three start-loss, and two splice site alterations) and in the RPL5 gene (four nonsense, three splice site variants, three frameshift, and one start-loss variant and one whole gene deletion). The most frequently mutated genes in the Russian Federation registry are RPS19, RPL5, and RPS7. Intriguing genotype-phenotype correlations were observed in patients with cleft palate and/or cleft lip: in four cases of six, LoF variants in the RPL5 gene were identified. There were two interesting cases of the DBA-like phenotype with novel mutations in the ADA2 and TSR2 genes. In both cases, red cell aplasia, hepatosplenomegaly, and onset in the first year of life were observed (7 and 6 months of age, respectively). Patient P151 presented with macrocytic anemia and reticulocytopenia and had a homozygous stop codon in the ADA2 gene. He also had erythema nodosum-like skin, recurrent fever, and reduced levels of T and B cells. The second patient, P162, had microcytic anemia and moderate thrombocytopenia and was hemizygous for a mutation in the TSR2 gene. Among other clinical features, low birth weight, atopic dermatitis, macrocrania, hypertelorism, depressed nasal bridge, and ventricular septal defect were observed. The proportion of our genetic findings located in RP genes is similar to those in other international cohorts with a large proportion of novel variants. In summary, the total efficiency of revealing causative variants in probands using three methods is 71.8% (107 out of 149). The combination of different molecular genetic approaches facilitates an improved diagnostic yield. The authors declare that there is no conflict of interest. This work was supported by grants from Charitable “Grand Life” Fund of Russian Federation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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