Brittany C. Thomas

Origins and prevalence of the American Founder Mutation of MSH2.

Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of approximately 500 years (95% confidence interval, 425-625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted.

The Value of MUTYH Testing in Patients with Early Onset Microsatellite Stable Colorectal Cancer Referred for Hereditary Nonpolyposis Colon Cancer Syndrome Testing

MUTYH adenomatous polyposis (MAP) can mimic both the familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) phenotypes. As a result of MAPs phenotypic overlap with FAP, some DNA diagnostic laboratories perform MUTYH testing in conjunction with APC testing in patients with suspected FAP or attenuated FAP (AFAP). In addition to testing FAP/AFAP samples for MUTYH mutations, we were interested whether there would also be value in testing samples referred for HNPCC testing. To determine this, we tested a consecutive series of 229 samples referred for HNPCC testing for the two most common MUTYH mutations in the Caucasian population. To enrich our study population with MAP cases, we only included samples from patients with early onset colorectal cancer (CRC diagnosed <50 years old) in whom HNPCC had been excluded by microsatellite instability testing (microsatellite stable or low microsatellite instability). Four biallelic (2%) and six monoallelic (3%) MUTYH mutation carriers were identified. No clinical factors predicted MUTYH mutation status. Specifically, a family history of vertical transmission of CRC or having few polyps (<15) did not rule out the possibility of biallelic MUTYH mutations. Thus, MUTYH mutation testing may be a reasonable cascade test in early onset CRC found to have proficient DNA mismatch repair, regardless of pattern of family history or number of polyps.

A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome

Purpose:The Muir–Torre syndrome variant of Lynch syndrome is characterized by the presence of sebaceous neoplasms (adenoma, epithelioma/sebaceoma, carcinoma) and Lynch syndrome–associated cancers (colon, endometrial, and others). Several clinical scoring systems have been developed to identify patients with colon cancer at high risk of Lynch syndrome. However, no such system has been described for patients presenting with sebaceous neoplasms.Methods:Based on logistic regression analysis, a scoring system was developed for patients with sebaceous neoplasm to identify those with the highest likelihood of having Muir–Torre syndrome. The final version of the scoring system included variables such as age at presentation of initial sebaceous neoplasm, total number of sebaceous neoplasms, personal history of a Lynch-related cancer, and family history of Lynch-related cancers.Results:Patients with a score of 3 or more were more likely to have Muir–Torre syndrome (28 of 29 patients), those with a score of 2 had intermediate likelihood (12 of 20 patients), and no patient with a score of 0 or 1 was diagnosed with Muir–Torre syndrome.Conclusion:The Mayo Muir–Torre syndrome risk scoring system appears to identify whether patients who present with sebaceous neoplasms are in need of further Lynch syndrome evaluation using easily ascertained clinical information. Abnormal mismatch repair gene immunohistochemistry of a sebaceous neoplasm is a poor predictor in regard to diagnosing Lynch syndrome.Genet Med 16 9, 711–716.

PMS2 monoallelic mutation carriers: the known unknown

Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors’ research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13–19.

Self Diagnosis of Lynch Syndrome Using Direct to Consumer Genetic Testing: A Case Study

We are reporting what we believe to be the first published case of patient initiated direct to consumer (DTC) genetic testing to test for the presence of a known familial mutation. Our client in this case is from a known MSH2 family; both his/her parent and associated grandparent have previously tested positive for the known familial MSH2 mutation. Using 23andme’s “family inheritance genome-wide comparison” option we were able to determine that our client most likely inherited the known familial MSH2 mutation without pursuing single site genetic testing. Our client pursued DTC genetic testing instead of single site genetic testing due to the fear of genetic discrimination. This case shows that patients are still fearful of genetic discrimination, despite the passage of the Genetic Information Nondiscrimination Act (GINA), and that DTC genetic testing may be useful despite the overall negative feeling towards this type of testing in the genetic counseling community.

Is Self-Disclosure Part of the Genetic Counselor's Clinical Role?

The role of genetic counselor self-disclosure in clinical practice is unclear as there are few published investigations of this issue. In the present study, 11 genetic counselors who previously received genetic services were interviewed about their opinions and use of disclosure. Several themes were extracted from their responses. All participants reportedly disclosed to patients; however, not all disclosed their receipt of genetic services. Patient requests for self-disclosure influenced many participants’ disclosure decisions. Opinions regarding potential benefits of disclosure varied. Nearly all participants stressed the importance of self-disclosing judiciously, stating that it may be counterproductive to client goal attainment. Four individuals with expertise in genetic counseling and psychotherapy were invited to react to these themes and to provide their opinions of self-disclosure. Their views are compared to those of the present sample, and practice and research recommendations are given.

Homozygosity for the V122I Mutation in Transthyretin Is Associated with Earlier Onset of Cardiac Amyloidosis in the African American Population in the Seventh Decade of Life

Individuals heterozygous for the V122I mutation in transthyretin (TTR) tend to develop cardiac amyloidosis, often after the seventh decade of life. Although homozygotes have been reported, these have typically been single case reports. We report a cohort of 13 V122I homozygotes. TTR gene sequencing results from the Mayo Clinic Molecular Genetics Laboratory between September 2004 and January 2013 were reviewed; 177 heterozygotes and 13 homozygotes for the V122I alteration were identified. Detailed clinical history was available for the 24 heterozygotes seen at Mayo Clinic. We compared age at onset of disease for this group to homozygotes, both alone and pooled with the 11 homozygotes from the literature. Individuals with homozygous V122I manifested symptoms a mean of 10 years earlier than heterozygotes (63.8 ± 5.7 versus 72 ± 8.1 yrs, P = 0.0002). Further, males were significantly overrepresented in both heterozygous and homozygous individuals. There was a trend for an even higher male bias in the homozygous group. All 24 homozygotes were African American, whereas four of the heterozygotes were reported as white. Two novel V122I compound heterozygotes were also identified, with clinical presentation in the late fifth or early sixth decade of life. This study is the largest homozygous V122I cohort reported and demonstrates association with earlier age at onset. It also highlights the uncertain penetrance, particularly with respect to sex.

The Utilization of Counseling Skills by the Laboratory Genetic Counselor

The number of available genetic testing options and the nuances associated with these options continue to expand. In addition, the scope of genetic testing has broadened to areas and specialties beyond Medical Genetics. In response to these changes, diagnostic laboratories have employed genetic counselors to help navigate the increasing complexity of genetic testing, given their expertise and training in human genetics. However a largely unrecognized aspect of this role involves the use of counseling skills. Counseling skills are used by laboratory genetic counselors in a variety of situations to convey information and facilitate understanding among clinicians and medical staff. This helps to reduce test ordering errors, promote optimal test utilization, and ensure best patient care practices. The specific counseling skills used by laboratory counselors will be explored using three fictional case vignettes, followed by a discussion of the applicability of these skills in other contexts. Exploration of the unique ways in which laboratory genetic counselors apply their counseling skills can be useful for professional development and instructive for graduate training programs.

“What Would You Do if You Were Me?” Effects of Counselor Self-Disclosure Versus Non-disclosure in a Hypothetical Genetic Counseling Session

Two prior studies suggest genetic counselors self-disclose primarily because patients ask them to do so (Peters et al., 2004; Thomas et al., 2006). However, scant research has investigated effects of counselor disclosure on genetic counseling processes and outcomes. In this study, 151 students (98 undergraduates, 53 graduates) completed one of three surveys describing a hypothetical genetic counseling session in which a patient at risk for FAP was considering whether to pursue testing or surveillance procedures. Dialogue was identical in all surveys, except for a final response to the question: “What would you do if you were me?” The counselor either revealed what she would do (Personal Disclosure), what other patients have done (Professional Disclosure), or deflected the question (No Disclosure). Imagining themselves as the patient, participants wrote a response to the counselor and indicated their perceptions of her. Participants rated the non-disclosing counselor significantly lower in social attractiveness than either disclosing counselor, and less satisfying than the professional disclosing counselor. Analysis of written responses yielded four themes: Made Decision, Sought Information, Expressed Thoughts/Feelings, and No Decision. Practice implications and research recommendations are provided.

An American founder mutation in MLH1

Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589‐2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (∼2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183–272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14–23); it accounts for 1.0% all LS in the Unites States and can be readily screened for.