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Enabling routine ?-thalassemia Prevention and Patient Management by scalable, combined Thalassemia and Hemochromatosis Mutation Analysis.

ABSTRACT: BACKGROUND:Beta (?)-thalassemia is one of the most common inherited disorders worldwide, with high prevalence in the Mediterranean, the Middle East and South Asia. Over the past 40?years, awareness and prevention campaigns in many countries have greatly reduced the incidence of affected child births. In contrast, much remains to be done in South-Asia. Thus, for Pakistan, an estimated ~?7000 children annually are born with thalassemia, with no sign of improvement. Although there is good agreement that intermarriage of carriers significantly contributes to the high prevalence of the disorder, effective tools for molecular screening and diagnosis on which to base prevention programs are not readily available. METHODS:Here, we present results for a novel LeanSequencing™ process to identify a combination of 18 ?-thalassemia mutations (including the sickle cell anemia mutation, HbS, and structural variants HbC and HbE) and 2 hemochromatosis mutations in a multi-ethnic population of 274 pediatric and adolescent patients treated at Afzaal Memorial Thalassemia Foundation in Karachi, Pakistan. RESULTS:We found substantial differences in the predominance of disease-causing mutations among the principal ethnic groups in our cohort. We also found the hemochromatosis mutation H63D C?>?G in 61 (or 22.1%) of our patients including 6 (or 2.2%) homozygotes. CONCLUSIONS:To our knowledge, this is the first screen combining a large set of ?-thalassemia and hemochromatosis mutations, so as to facilitate the early identification of patients who may be at increased potential risk for complications from iron overload and thereby to improve the prospective management of thalassemia patients.

SUBMITTER: Hashmi G

PROVIDER: S-EPMC7229588 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Enabling routine β-thalassemia Prevention and Patient Management by scalable, combined Thalassemia and Hemochromatosis Mutation Analysis.

Hashmi Ghazala G Qidwai Asim A Fernandez Kristopher K Seul Michael M

BMC medical genetics 20200515 1

<h4>Background</h4>Beta (β)-thalassemia is one of the most common inherited disorders worldwide, with high prevalence in the Mediterranean, the Middle East and South Asia. Over the past 40 years, awareness and prevention campaigns in many countries have greatly reduced the incidence of affected child births. In contrast, much remains to be done in South-Asia. Thus, for Pakistan, an estimated ~ 7000 children annually are born with thalassemia, with no sign of improvement. Although there is good a ...[more]

PMID: 32414341

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Project description:Background Neonatal hemochromatosis causes acute liver failure during the neonatal period, mostly due to gestational alloimmune liver disease (GALD). Thalassemia causes hemolytic anemia and ineffective erythropoiesis due to mutations in the globin gene. Although neonatal hemochromatosis and thalassemia have completely different causes, the coexistence of these diseases can synergistically exacerbate iron overload. We report that a newborn with εγδβ-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation. Case presentation A 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδβ-thalassemia by genetic testing, and required frequent red blood cell transfusions. At 2 months after birth, exacerbation of jaundice, grayish-white stool, and high serum ferritin levels were observed, and liver biopsy showed iron deposition in hepatocytes and Kupffer cells. Magnetic resonance imaging scans showed findings suggestive of iron deposits in the liver, spleen, pancreas, and bone marrow. The total amount of red blood cell transfusions administered did not meet the criteria for post-transfusion iron overload. Administration of an iron-chelating agent was initiated, but iron overload rapidly progressed to liver failure without improvement in jaundice and liver damage. He underwent living-donor liver transplantation from his mother, after which iron overload disappeared, and no recurrence of iron overload was observed. Immunohistochemical staining for C5b-9 in the liver was positive. Serum hepcidin levels were low and serum growth differentiation factor-15 levels were high prior to living-donor liver transplantation. Conclusions We reported that an infant with εγδβ-thalassemia developed NH due to GALD, and that coexistence of ineffective erythropoiesis in addition to erythrocyte transfusions may have exacerbated iron overload. Low serum hepcidin levels, in this case, might have been caused by decreased hepcidin production arising from fetal liver damage due to neonatal hemochromatosis and increased hepcidin-inhibiting hematopoietic mediators due to the ineffective hematopoiesis observed in thalassemia. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-022-03706-3.

Project description:Introduction Thalassemia is a genetically complex disorder that evolves from a mutation in the beta chain of hemoglobin. Much work has been done on the common mutations, but some rare mutations have been found that impact and diversify the disease spectrum. Case presentation Our case report is on a young adult who presented with anemia, gall stones, and off-and-on transfusion dependency. A detailed workup revealed that the patient was suffering from thalassemia intermedia. The interesting finding was that the patient, product of non-consanguineous marriage was homozygous for beta thalassemia mutation on genetic analysis. A detailed genetic analysis of the parents revealed them as carriers for the same mutation. It was found that patient was homozygous for a rare and novel mutation −88(C > A)[HBB:c.-138C > A] on whole gene sequencing. Discussion The area of genomics in thalassemia is rapidly growing, and our case report aims to update the current knowledge of thalassemia's genomic information in Pakistan. The mutation found in our patient was −88(C > A)[HBB:c.-138C > A], and the data provided by the National Library of Medicine for this mutation as Allele ID: 380597 and variant type of single nucleotide variant shows that only ten such cases exist in the world with this rare mutation. Our case would be the 11th case in the world and 1st in Pakistan according to the literature, reporting above mentioned mutation. Conclusion Further translational study is required to accurately utilize genomic data as an instrument of precision treatment in thalassemia patients, especially in underdeveloped countries like Pakistan. Highlights • Thalassemia evolves from a mutation in the beta chain of hemoglobin transferred mostly from parents to children or rarely a de novo mutation might occur.• Globally there are more than 535 gene mutations in beta chain of hemoglobin with common ones in Pakistan being IVSI-1,IVSI-5, IVSII-1, del 619, Fr 8–9, Fr 16, Fr 41–42.• Our case report is about a thalassemia patient having a rare mutation in beta globin gene of hemoglobin on genetic analysis.

Dataset Information

Enabling routine ?-thalassemia Prevention and Patient Management by scalable, combined Thalassemia and Hemochromatosis Mutation Analysis.

Publications

Enabling routine β-thalassemia Prevention and Patient Management by scalable, combined Thalassemia and Hemochromatosis Mutation Analysis.

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