WBR0385

Author	[[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D. and Alison Leibowitz [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Renal
Prompt	[[Prompt::A 12-year-old boy is brought by his mother to the physician’s office for red-colored urine. Upon further questioning, the mother explains that her son is deaf and has eye problems. The physician suspects a collagen disease. Genetic studies reveal a mutation of COL4A5 and confirm the diagnosis with mutation encoding α chains. Which of the following is most likely the mode of inheritance of this patient’s condition?]]
Answer A	AnswerA::X-linked dominant
Answer A Explanation	AnswerAExp::Alport Syndrome (AS) can be inherited in an X-linked pattern due to a mutation in ''COL4A5''.
Answer B	AnswerB::Autosomal recessive
Answer B Explanation	AnswerBExp::Mutations in ''COL4A3'' and ''COL4A4'' that result in AS are usually inherited in an autosomal recessive pattern.
Answer C	AnswerC::Autosomal dominant
Answer C Explanation	AnswerCExp::Alport syndrome is rarely inherited in an autosomal dominant pattern.
Answer D	AnswerD::Mitochondrial
Answer D Explanation	AnswerDExp::Alport syndrome is not a mitochondrial disease. Examples of mitochondrial diseases are MELAS and MERRF.
Answer E	AnswerE::Polygenic
Answer E Explanation	[[AnswerEExp::Alport syndrome is not considered a polygenic disease. Common polygenic diseases include schizophrenia and heart disease. Polygenic disease refers to a disease in which multiple genetic loci are thought to contribute to disease risk in the same individual (many risk/protective alleles of low affect size). This concept is distinct from the idea of locus heterogeneity, where mutations in separate genes can cause the same Mendelian syndrome. Alport syndrome and hypertrophic cardiomyopathy are examples of Mendelian diseases with locus heterogeneity.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Alport Syndrome (AS) is an inherited disorder of type IV collagen with thinning and splitting of glomerular basement membranes, hematuric nephropathy, and sensorineural deafness. Alport Syndrome may be caused by mutations in several genes of the collagen family (locus heterogeneity), including COL4A3, COL4A4, and COL4A5. More than 80% of cases of Alport syndrome are caused by mutations in COL4A5, a gene that encodes the α5 subunit of basement membrane-associated collagen type IV. COL4A5 is located on the X chromosome, and Alport syndrome related to this locus therefore follows an X-linked dominant mode of inheritance. COL4A3 and COL4A4, which encode α3 and α4 respectively, are located on chromosome 2. Alport syndrome that results from mutations in COL4A3 and COL4A4 usually follows an autosomal recessive pattern of inheritance. Autosomal dominant pattern of inheritance is rare. Educational Objective: Alport Syndrome (AS) is usually inherited in an X-linked dominant pattern due to a mutation in COL4A5. Less commonly, it is inherited in an autosomal recessive pattern due to a mutation in COL4A3 or COL4A4. References: Haas M. Alport syndrome and thin glomerular basement membrane nephropathy. A practical approach to diagnosis. Archives of Pathology and Laboratory Medicine. 2009;133(2):224-232. Hasstedt SJ, Atkin CL. X-linked inheritance of Alport syndrome: family P revisited. Am J Hum Genet. 1983;35:1241-1251. First Aid 2014 page 538]]
Approved	Approved::Yes
Keyword	WBRKeyword::Genetics, WBRKeyword::Deafness, WBRKeyword::Blind, WBRKeyword::Hematuria, WBRKeyword::X-linked, WBRKeyword::X-linked dominant, WBRKeyword::COL4A5, WBRKeyword::Basement membrane, WBRKeyword::Alport syndrome
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::