WBR0150

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Hematology
Prompt	[[Prompt::A 7-year-old boy is brought to his pediatrician with fatigue and pallor. The patient recently emigrated from Greece, and his parents report that he has a long history of hospitalizations. When he became very ill in the past, he was transferred to the hospital and was given multiple blood transfusions. Complete blood count is remarkable for a hemoglobin of 5.7 g/dL, white blood cell count of 12.7x109 /L, platelet count of 250 x 109 /L, and mean corpuscular volume of 66 fL. The child is unusually small and has a pronounced forehead. A radiograph of the skull is shown in the image below. What is the most likely type of mutation that is responsible for this patient’s disease? ]]
Answer A	AnswerA::Splice site mutation
Answer A Explanation	AnswerAExp::Beta-thalassemia is most often caused by splice site mutations in the beta-globin gene.
Answer B	AnswerB::Nonsense mutation
Answer B Explanation	[[AnswerBExp::Nonsense mutations introduce a premature stop codon in the gene. An example of a disorder caused by germline nonsense mutations is Duchenne Muscular Dystrophy.]]
Answer C	AnswerC::Missense mutation
Answer C Explanation	AnswerCExp::Missense mutation is a point mutation where a change in a single nucleotide leads to the formation of a codon that codes for a different amino acid. An example of a disorder caused by germline nonsense mutations is Becker Muscular Dystrophy.
Answer D	AnswerD::Gene deletion
Answer D Explanation	AnswerDExp::Gene deletion is defined as loss of part of the gene or sequences of the DNA within a chromosome. An example of a disorder caused by large deletions is Duchenne Muscular Dystrophy.
Answer E	AnswerE::Gene silencing
Answer E Explanation	[[AnswerEExp::Gene silencing is an epigenetic regulation of gene expression, where chromosomal DNA expression is shut down. It is most often achieved by methylation of the gene promoter. An example of a disorder caused by gene silencing is Prader-Willi syndrome.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Beta-thalassemia is a hereditary hemoglobinopathy that is characterized by a quantative decrease in the production of beta-globin chains. Beta-thalassmia is caused by splice site mutations in the beta-globin gene. It is prevalent among Mediterranean populations. A splice site mutation is defined as a genetic mutation that results in the insertion, deletion, or alteration of a number of nucleotides occurs while splicing introns during processing of precursor mRNA into mature mRNA. In thalassemia, point mutations commonly occur in an intron, which leads to the activation of aberrant splicing sites. If both alleles of the beta-globin gene have thalassemia mutations, the diagnosis of beta-thalassemia major is made. Beta-thalassemia major is a severe microcytic, hypochromic anemia. Beta-thalassemia is a clinically heterogeneous disease that causes anemia with ineffective erythropoiesis, hepatosplenomegaly, and severe bone deformities. It often progresses to death before the age of 20 years. A hallmark feature of beta-thalassemia major is the “buzz cut” or “hair on end” appearance of the skull on X-ray. This increased spiky opacity is caused by bone marrow expansion in response to chronic anemia (extramedullary hematopoeisis). Treatment consists of periodic blood transfusion, splenectomy in cases of splenomegaly, and treatment of transfusion-induced iron overload with chelation therapy. Cure is possible only by bone marrow transplantation. The following table distinguishes the various forms of beta-thalassemia based on genetic characteristics, clinical manifestations, and relevant genetic factors that affect disease severity: Educational Objective: Beta-Thalassemia is caused by splice site mutations in the beta-globin gene. References: Danckwardt S, Neu-Yilik G, Thermann R, et al. Abnormally spliced β-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay. Blood. 2002;99(5):1811-6. Lewis J, Yang B, Kim R, et al. A common human β globin splicing mutation modeled in mice. Blood. 1998;91(6):2152-6. Rund D, Rachmilewitz E. β-thalassemia. N Engl J Med. 2005;353:1135-46 First Aid 2014 page 383]]
Approved	Approved::Yes
Keyword	WBRKeyword::Blood, WBRKeyword::Hematology, WBRKeyword::Genetics, WBRKeyword::Thalassemia, WBRKeyword::Beta thalassemia, WBRKeyword::Transfusion, WBRKeyword::Iron, WBRKeyword::Mutation, WBRKeyword::Beta-thalassemia major, WBRKeyword::Beta-thalassemia, WBRKeyword::Beta thalassemia major, WBRKeyword::Splice Site, WBRKeyword::Intron
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::