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Alberto Falchetti, a clinical endocrinologist and medical geneticist at the University Hospital of Careggi in Florence, Italy, has written extensively on genetic testing for mutations related to multiple endocrine neoplasia type 1 — a rare, autosomal-dominant disorder characterized by tumors in two or more endocrine tissues. Because nearly 90 percent of MEN1 patients have an affected parent, Falchetti advocates genetic testing to identify MEN1 mutations in carriers' relatives. Genome Technology's Tracy Vence recently spoke with him to discuss MEN1 genetic testing and clinical care.

Genome Technology: How is multiple endocrine neoplasia type 1 typically diagnosed?

Alberto Falchetti: The diagnosis of MEN1 is still a clinically based diagnosis. … The unraveling of germline MEN1 mutations in a proband can confirm the clinical diagnosis.

GT: What was the conventional clinical scenario before MEN1 genetic testing?

AF: Without MEN1 genetic testing, the diagnosis of MEN1 syndrome was, and is likely to be, delayed or missed … [and] was made only after there was evidence of clinical manifestations — generally several years after the onset of tumors … unless there was a clearly evident positive familial history.

GT: What are some of the intricacies of MEN1 germline mutations that can complicate the molecular detection process?

AF: MEN1 germline mutations are identified in about 80 to 90 percent of probands with familial MEN1 syndrome and about 65 percent of individuals with simplex MEN1 syndrome. Simplex MEN1 cases are less likely to test positive than familial cases, in part because some of these are caused by somatic mosaicism. When germline mutations consist of large deletions, their identification is not always easy. Between 1 and 3 percent of MEN1 germline mutations may be large deletions. Also, intronic MEN1 mutations may complicate the molecular screening process. They represent splicing affecting genomic variants that are likely significant in the 10 percent of individuals with MEN1 syndrome who do not have coding-region mutations.

GT: In an F1000 Medicine Reports paper, you list specific criteria that a clinician should consider before ordering MEN1 testing for his patient. How important are genetic counseling and familial follow-up?

AF: Approximately 90 percent of individuals diagnosed with MEN1 syndrome have an affected parent and 10 percent have de novo mutations. The probability of finding a mutation is correlated with the number of MEN1-related tumors … and increases in [the] presence of a positive family history. Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing. … [An affected individual's] family history may appear to be negative because of failure to recognize the disorder in family members. Genetic testing can only be used for at-risk relatives if a disease-causing germline mutation has been identified in an affected family member. When a known disease-causing mutation is not identified, linkage or haplotype analysis can be considered in families with more than one affected family member. Because early detection of at-risk individuals affects medical management, testing of individuals during childhood — who have no symptoms — is beneficial.

GT: Are there data to suggest that genetic testing can inform medical management?

AF: In general, genetic testing has decreased the morbidity and mortality associated with MEN1. A prospective clinical study on carriers of the mutant MEN1 gene [showed that it is] possible to identify the bio-chemical evidence of cancer, on average, 10 years before its clinical presentation, allowing early surgical intervention. [This justifies] routine surveillance of asymptomatic carriers of germline MEN1 mutation and others at risk for developing cancers associated with MEN1.

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