Sorted By Test Name - Mayo Medical Laboratories

HNPCC
17073
overall incidence of HHT in North America is estimated to be between 1:5,000 and 1:10,000. Penetrance
seems to be age related, with increased manifestations occurring over oneâ€s lifetime. For example,
approximately 50% of diagnosed individuals report having nosebleeds by age 10 years, and 80% to 90%
by age 21 years. As many as 90% to 95% of affected individuals eventually develop recurrent epistaxis.
Two genes are most commonly associated with HHT: the endoglin gene (ENG), containing 15 exons and
located on chromosome 9 at band q34; and the activin A receptor, type II-like 1 gene (ACVRL1 or
ALK1), containing 10 exons and located on chromosome 12 at band q1. Mutations in these genes occur in
about 80% of individuals with HHT. ENG and ACVRL1 encode for membrane glycoproteins involved in
transforming growth factor-beta signaling related to vascular integrity. Mutations in ENG are associated
with HHT type 1 (HHT1), which has been reported to have a higher incidence of pulmonary AVMs,
whereas ACVRL1 mutations occur in HHT type 2 (HHT2), which has been reported to have a higher
incidence of hepatic AVMs. It has been suggested that HHT1 has a more severe phenotype compared to
HHT2. ENG gene, known mutation testing is for the genetic testing of individuals who are at risk for an
ENG mutation that has been previously identified in the family. If the familial mutation is not known, the
familial proband should be screened for ENG and ACVRL1 mutations via full gene analyses
(HHTP/89394 Hereditary Hemorrhagic Telangiectasia, ENG and ACVRL1 Full Gene Analysis). Once a
mutation has been identified in a family, known mutation analysis can be performed in at-risk family
members. HHT is phenotypically heterogeneous both between families and amongst affected members of
the same family. Furthermore, complications associated with HHT have variable ranges of age of onset.
Thus, HHT can be diagnostically challenging. Genetic testing for ENG and ACVRL1 mutations allows
for the confirmation of a suspected genetic disease. Confirmation of HHT diagnosis will allow for proper
treatment and management of the disease, preconception/prenatal counseling, and family counseling. In
addition, it has been estimated that genetic screening of suspected HHT individuals and their families is
more economically effective than conventional clinical screening.(1)
Useful For: Genetic testing of individuals at risk for a known endoglin gene (ENG) familial mutation
(associated with hereditary hemorrhagic telangiectasia)
Interpretation: An interpretive report will be provided.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Cohen JH, Faughnan ME, Letarte M, et al; Cost comparison of genetic and
clinical screening in families with hereditary hemorrhagic telangiectasia. Am J Med Genet
2005;137A:153-160 2. Sabba C, Pasculli G, Lenato GM, et al: Hereditary hemorrhagic telangiectasia:
clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007; 5:1149-1157 3. Abdalla
SA, Letarte M: Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of
disease. J Med Genet 2006;43:97-110 4. Guttmacher AE, Marchuk DA, White RI Jr: Hereditary
hemorrhagic telangiectasia. N Engl J Med 1995;333:918-924 5. Bayrak-Toydemir P, Mao R, Lewin S, et
al: Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era
for clinicians. Genet Med 2004;6:175–191
Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Screen
Clinical Information: Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch
syndrome, is an autosomal dominant inherited cancer syndrome that predisposes individuals to the
development of colorectal, endometrial, gastric, upper urinary tract, and other cancers. Individuals with
HNPCC/Lynch syndrome have a germline mutation in 1 of several genes involved in DNA mismatch
repair. The majority of mutations associated with HNPCC/Lynch syndrome occur in MSH2 and MLH1;
however mutations in MSH6 and PMS2 have also been identified. There are several strategies for
evaluating individuals whose personal and/or family history of cancer is suggestive of HNPCC/Lynch
syndrome. Testing the tumors from individuals at risk for HNPCC/Lynch syndrome for microsatellite
instability (MSI) demonstrates the presence or absence of defective DNA mismatch repair within the
tumor. Individuals whose tumors demonstrate the presence of defective DNA mismatch repair in the form
of microsatellite instability are more likely to have a germline mutation in one of the mismatch repair
genes, MLH1, MSH2, MSH6, and PMS2. Tumors from affected individuals usually demonstrate an
MSI-H phenotype (MSI >30% of microsatellites examined), whereas tumors from individuals who do not
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