WBR0100

Author	[[PageAuthor::William J Gibson (reviewed by Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::General Principles
Prompt	[[Prompt::A 4 year old boy in Brazil has immigrated to the United States with his family. His mother reports that the boy has begun bumping into furniture very often, and has concerns that his vision may be compromised. She shows you an image in which the pupil of his left eye has a bright reflection due to the camera flash. Upon further questioning, it is revealed that the boy’s father underwent surgery at a young age, leaving him blind in both eyes. The offending lesion is surgically removed and the tissue is analyzed for molecular genetic features. Chromosome 13 displays a normal karyotype. A set of common single nucleotide polymorphisms (SNPs) on chromosome 13q is profiled and the resulting SNP identities are displayed below. Assume all of the SNPs have an allelic fraction in the general population of approximately 50%. The RB1 gene spans positions 48,934,153-48,951,170 on chromosome 13. Which of the following molecular events most likely occurred in the boy’s somatic tissues to cause his condition? SNP ID Chromosome Genomic Position Genotype rs4771054 13 27562342 CC rs17626553 13 28968770 CT rs2776961 13 30101280 GT rs144430040 13 31085367 CC rs4941731 13 33568060 GG rs9528533 13 34588335 CT rs9548644 13 39720610 AA rs9315803 13 41623184 GT rs9634767 13 42270305 CT rs2044732 13 42833400 AG rs17536002 13 43035209 TT rs11619528 13 44826355 TT rs12866473 13 46037501 CC rs1413077 13 47875303 AA rs7329865 13 49154165 AA rs895967 13 49347566 GG rs2191226 13 50940143 AA rs4943003 13 52090383 GG rs476136 13 53413498 GG rs10507581 13 54154463 GG rs9591632 13 55611511 CC rs4885962 13 56863954 AA rs2592866 13 58226942 GG rs1411645 13 59052343 CC rs6562010 13 59711493 TT ]]
Answer A	AnswerA::Mutation
Answer A Explanation	[[AnswerAExp::While a de novo mutation causing a “second hit” to the retinoblastoma gene is possible, there is no evidence that this has occurred. The SNPs above clearly show recombination on chromosome 13, making loss of heterozygosity most likely.]]
Answer B	AnswerB::Gene Deletion
Answer B Explanation	AnswerBExp::While a deletion of the wild type allele of the Rb gene could cause the “second hit” to the Rb gene, the normal karyotype of chromosome 13 makes this possibility less likely.
Answer C	AnswerC::Mitotic recombination
Answer C Explanation	[[AnswerCExp::Note that all of the SNPs after rs2044732 are homozygous. We know that there are two copies of chromosome 13 remaining from the karyotype, so the only possibilities are: 1. The child is homozygous for all of these alleles in the germline or 2. Chromosome 13q underwent mitotic recombination. Possibility 1 is unlikely, because as was stated in the question prompt, all of these alleles have an allelic fraction of around 50%. Therefore, the probability of 15 homozygous alleles in a row is (0.5)^15 = 0.00003 (ie very unlikely).]]
Answer D	AnswerD::Gene duplication
Answer D Explanation	[[AnswerDExp::There is no evidence for duplication of the RB gene, and such a duplication would not be expected to cause a retinoblastoma tumor.]]
Answer E	AnswerE::Methylation
Answer E Explanation	[[AnswerEExp::While methylation is responsible for silencing genes, methylation is most associated with Prader-Willi syndrome and Angelman syndrome. There is no evidence for gene methylation in this question, but there is clear evidence of mitotic recombination leading to loss of heterozygosity.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient in this vignette has familial retinoblastoma, a rapidly developing cancer that develops from the immature cells of a retina, caused by defects in the retinoblastoma gene on chromosome 13. Children often have germline mutations in the retinoblastoma protein which can be passed down to descendents. The retinoblastoma protein functions as a tumor suppressor, and therefore the sole germline mutation acts as a recessive trait at the cellular level. A “second hit” which alters the remaining wild type allele in somatic tissues is required for the initiation of tumorigenesis. In this case, we have clear evidence of mitotic recombination in which the maternal chromosome 13 has been replaced by the paternal alleles after rs2044732. Thus, the cell which inherits both paternal alleles has no wild type retinoblastoma protein and will go on to form a tumor. Familial retinoblastoma functions as an autosomal dominant trait, as the probability of a second hit in somatic tissues is certain due to the number of cells in the developing retina. Patients with familial retinoblastoma have an increased risk of other tumors such as osteosarcomas. Educational Objective: Loss of heterozygosity is a common mechanism for the "second-hit" in tumor suppressor gene inactivation. References: First Aid 2014 page 84]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Genetics, WBRKeyword::Tumor suppressor, WBRKeyword::Retinoblastoma, WBRKeyword::Tumor
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