Biobanks and archived datasets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings (IFs) and individual research results (IRRs) of potential health, reproductive, or personal importance to individual contributors (using “biobank” here to refer to both collections of samples and collections of data). This paper reports recommendations from a 2-year, NIH-funded project. The authors analyze responsibilities to manage return of IFs and IRRs in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). They suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When re-identification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities: to (1) clarify the criteria for evaluating findings and roster of returnable findings, (2) analyze a particular finding in relation to this, (3) re-identify the individual contributor, and (4) recontact the contributor to offer the finding. The authors suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and that are clinically actionable should generally be offered to consenting contributors. The paper specifies 10 concrete recommendations, addressing new biobanks and biobanks already in existence.
incidental findings; return of results; biobanks; research ethics; bioethics; genetics; genomics
Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. While sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as LFS- associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer (GC) in LFS.
Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute LFS registry. We identified subjects with GC documented either by pathology report or death certificate, and performed pathology review of the available specimens.
Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. GC was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at GC diagnosis were 43 and 36 years, respectively (range 24-74 years), significantly younger compared to the median age at diagnosis in the general population based on SEER data (71 years). Five (8.1%) families reported 2 or more cases of GC and 6 (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies.
Early-onset GC appears to be a component of LFS, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of GC.
Li Fraumeni syndrome; gastric cancer; hereditary gastric cancer syndromes; germline mutations; TP53
Genotype-driven research recruitment complicates traditional study roles and may leave those recruited worried about unwelcome surprises from their DNA. This study investigated the ways that individuals experience genotype-driven recruitment, and conceptualize their roles as research participants.
Individual interviews were conducted with the participants of a genotype-driven study on cystic fibrosis. The eligibility criteria included the presence of one of two genetic variants. We interviewed 24 of these participants: 9 had cystic fibrosis and 15 had been selected from a biobank as “healthy volunteers.”
Participants with cystic fibrosis expressed no concerns about the eligibility criteria and saw themselves as part of a close-knit research community. However, biobank participants were unsure about why they had been selected and how they should think about themselves relative to the study. They sometimes reacted with anxiety to genetic information that they perceived to connect them with cystic fibrosis.
Being recruited for a study on the basis of one’s genotype may raise uncertainties about the meaning and implications of the genotypic information. People without the disease under study may require especially clear and detailed explanations of what researchers already know about their genetic makeup, in terms of future risk for themselves or their children.
case–control study; eligibility determination; genotype-driven research; individual research results; research recruitment
The purpose of this qualitative analysis was to assess parental acceptability of large-scale, telephone follow-up regarding their infants' newborn screening (NBS) results indicating carrier status for sickle cell hemoglobinopathy (SCH) and cystic fibrosis (CF).
Analysis of 195 interview transcripts focused on parents' responses to two open-ended questions “What was your reaction to being called by me?” and “What do you think of the state newborn screening program having follow-up people calling parents like you?” Responses were coded using conventional content analysis procedures and non-parametric tests were performed to analyze quantitative data.
Most parents reported favorable opinions about the follow-up. Favorable opinions were associated with several emotional reactions to receiving follow-up (p<0.001), and three reasons why parents found the interview beneficial (p<0.05): it provided information, clarified NBS results, and answered questions. Seventeen parents of SCH carriers reportedly had not been told their infant's NBS results and received them for the first time during the follow-up interview.
Parents of CF and SCH carrier infants had favorable opinions and identified specific benefits to receiving follow-up contact. This analysis demonstrates an information deficit among carrier parents and illustrates the importance of NBS follow-up and need for comprehensive communication and counseling.
newborn screening; follow-up counseling; cystic fibrosis carrier; sickle cell trait; provider-patient communication
The increased sensitivity of chromosomal microarray (CMA) technology as compared with traditional cytogenetic analysis allows for improved detection of genomic alterations. However, there is potential for uncertainty in the interpretation of test results in some cases. This paper explores how families understand and make meaning of CMA test results, and identifies the needs of families undergoing CMA testing.
We conducted semistructured interviews with parents of 25 pediatric outpatients with CMA test results indicating either a pathogenic alteration or a variant of unknown significance (VUS). Interviews were analyzed qualitatively.
Three domains of understanding were identified: comprehension of results, interpretations of scientific uncertainty, and personal meaning for the child and family. Incomplete comprehension of test results and scientific uncertainty were prominent themes for families receiving results in both the VUS and pathogenic categories. Receiving results from non-geneticists and by telephone, long waits to see a geneticist, and misleading Internet searches all contributed to misunderstandings.
Differentiating domains of understanding allows for the identification of uncertainties that can be reduced or managed in order to improve understanding of CMA results. Using this framework, we suggest interventions to promote clarity and address the informational needs of families undergoing CMA testing.
comprehension; genetic testing; health communication; qualitative; uncertainty
Understanding how sequence variants within healthy genomes are distributed with respect to ethnicity and disease-implicated genes is an essential first step toward establishing baselines for personalized genomic medicine.
In this study, we present an analysis of 10 genomes from healthy individuals of various ethnicities, produced using six different sequencing technologies. In total, these genomes contain more than 34 million single-nucleotide variants.
We have analyzed these variants from a clinical perspective, assaying the influence of sequencing technology and ethnicity on prognosis. We have also examined the utility of OMIM and the disease-gene literature for determining the impact of rare, personal variants on an individual’s health.
Our analyses demonstrate that clinical prognoses are complicated by sequencing platform-specific errors and ethnicity. We show that disease-causing alleles are globally distributed along ethnic lines, with alleles known to be disease causing in Eurasians being significantly more likely to be homozygous in Africans.
personal genomes; genome analysis; personalized genomics
Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder.
Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed.
Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms—such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication—as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsuflciency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype.
Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies.
aCGH; CdLS; CNV; genomic rearrangement; NIPBL
Next-generation sequencing (NGS) has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings.
We categorized 2016 genes linked with Mendelian diseases into “bins” based on clinical utility and validity, and used a computational algorithm to analyze 80 whole genome sequences in order to explore the use of such an approach in a simulated real-world setting.
The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database (HGMD) improved the yield for missense mutations, but also revealed that a substantial proportion of purported disease-causing mutations were misleading.
This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pre-test informed consent, laboratory analysis, and post-test return of results in a clinical context.
Whole genome sequencing; whole exome sequencing; clinical informatics; incidental findings; secondary findings
To determine caregiver perceptions about population screening for fragile X and examine factors potentially associated with support for screening.
We asked 1,099 caregivers of a child with fragile X syndrome or a fragile X carrier to rate whether free, voluntary screening should be offered preconception, prenatally, neonatally, or when problems occur. Caregivers chose a preferred time for screening, reported whether screening would affect parent–child bonding, indicated preferences for carrier detection, and gave reasons for their choices.
Caregivers endorsed all forms of screening, but prenatal screening was less strongly endorsed than preconception or postnatal screening. Most (79%) preferred preconception carrier testing, allowing more options when making reproductive decisions. Most thought that screening should also disclose carrier status and believed a positive screen would not negatively affect parent–child bonding. Maternal education, caregiver depression, family impact, and severity of disability were not associated with screening opinions, but parents who only had carrier children were less likely to endorse prenatal screening.
Caregivers of children with fragile X widely endorse screening. But because different parents will make different choices, screening may need to be offered at multiple times with careful consideration of consent and informed decision making.
Examination of patients’ responses to direct-to-consumer genetic susceptibility tests is needed to inform clinical practice. This study examined patients’ recall and interpretation of, and responses to, genetic susceptibility test results provided directly by mail.
This observational study had 3 prospective assessments (before testing; 10 days after receiving results; 3 months later). Participants were 199 patients aged 25–40 who received free genetic susceptibility testing for 8 common health conditions.
Over 80% correctly recalled their results for the 8 health conditions. Patients were unlikely to interpret genetic results as deterministic of health outcomes (mean=6.0, SD=0.8 on 1–7 scale, 1 indicating strongly deterministic). In multivariate analyses, patients with the least deterministic interpretations were White (p=.0098), more educated (p=.0093), and least confused by results (p=.001). Only 1% talked about their results with a provider.
Findings suggest that most patients will correctly recall their results and will not interpret genetics as the sole cause of diseases. The subset of those confused by results could benefit from consultation with a health care provider, which could emphasize that health habits currently are the best predictors of risk. Providers could leverage patients’ interest in genetic tests to encourage behavior changes to reduce disease risk.
Direct-to-consumer genetic tests; genetic testing; understanding; provider-patient communication; public health genomics
Gaucher disease (GD) carrier screening is controversial in the medical community. The goal of this study was to explore prenatal healthcare providers’ current GD carrier screening practices.
Prenatal healthcare providers were invited by email to complete an electronic-based survey.
A total of 1454 prenatal healthcare providers, including 209 genetic counselors, 450 midwives, and 795 physicians, completed the study. The majority of genetic counselors (n=208/209, >99%), physicians (n=415/450, 92%), and midwives (n=634/795, 80%) currently offer Jewish ancestry disease carrier screening to couples in whom one or both partners are Jewish. Of providers who offer Jewish ancestry disease screening, the majority of genetic counselors (n=199/208, 96%) and physicians (n=352/415, 85%) always or sometimes offer GD screening whereas the majority of midwives (n=357/634, 56%) never offer GD screening.
This study presents the first report of prenatal healthcare providers’ GD carrier screening practices in North America. Our results indicate that GD carrier screening is being offered at a high rate within the scope of Jewish ancestry-based carrier screening. This may highlight a need to move away from the debate as to whether GD carrier screening should be offered and, instead, focus on how best to provide GD carrier screening services.
Gaucher disease; prenatal healthcare providers; carrier screening; practices; survey
To assess whether reactions to genetic explanations for disparities in lung cancer incidence among family members of African American patients with lung cancer are associated with willingness to participate in clinical genetics research.
Data are reported for 67 self-identified African Americans ages 18 to 55 years who completed a telephone survey assessing reactions to explanations (i.e., genetics, toxin exposure, menthol cigarettes, race-related stress) for lung cancer disparities. Majority was female (70%), current smokers (57%), and patients’ biological relatives (70%).
Family members’ rated the four explanations similarly, each as believable, fair and not too worrisome. Participants also indicated a high level of willingness to participate in genetics research (M= 4.1 ± 1.0; Scale 1–5). Endorsements of genetics explanations for disparities as believable and fair, and toxin exposure as believable were associated significantly with willingness to participate in genetics research.
These results suggest that strategies to encourage African Americans’ participation in genetics research would do well to inform potential participants of how their involvement might be used to better understand important environmental factors that affect health disparities.
African Americans; lung cancer disparities; willingness to participate; clinical genetics research; psychosocial factors
Return of individual research results from genomic studies is a hotly debated ethical issue in genomic research. However, the perspective of key stakeholders—Institutional Review Board (IRB) reviewers—has been missing from this dialogue. This study explores the positions and experiences of IRB members and staff regarding this issue.
In depth interviews with 31 IRB professionals at six sites across the United States.
IRB professionals agreed that research results should be returned to research participants when results are medically actionable but only if the participants wanted to know the result. Many respondents expected researchers to address the issue of return of results (ROR) in the IRB application and informed-consent document. Many respondents were not comfortable with their expertise in genomics research, and only a few described actual experiences in addressing ROR. Although participants agreed that guidelines would be helpful, most were reticent to develop them in isolation. Even where IRB guidance exists (e.g., CLIA lab certification required for return), in practice, the guidance has been overruled to allow return (e.g., no CLIA lab performs the assay).
An IRB-researcher partnership is needed to help inform responsible and feasible institutional approaches to returning research results.
return of results; disclosure of results; genomic research; genetic research; Institutional Review Boards
Despite growing concerns toward maintaining participants’ privacy, individual investigators collecting tissue and other biological specimens for genomic analysis are encouraged to obtain informed consent for broad data sharing. To assess the effect on research enrollment and data sharing decisions of three different consent types (traditional, binary, or tiered) with varying levels of control and choices regarding data sharing.
A single blind, randomized controlled trial was conducted with 323 eligible adult participants being recruited into one of six genome studies at Baylor College of Medicine in Houston, Texas between January 2008 and August 2009. Participants were randomly assigned to one of three experimental consent documents (traditional, n=110; binary, n=103; tiered, n=110). Debriefing in follow-up visits provided participants a detailed review of all consent types and the chance to change data sharing choices or decline genome study participation.
Before debriefing, 83.9% of participants chose public data release. After debriefing, 53.1% chose public data release, 33.1% chose restricted (controlled access database) release, and 13.7% opted out of data sharing. Only one participant declined genome study participation due to data sharing concerns.
Our findings indicate that most participants are willing to publicly release their genomic data, however, a significant portion prefer restricted release. These results suggest discordance between existing data sharing policies and participants’ judgments and desires.
data sharing; genome research; ethical issues; participant perspectives; consent
Congenital disorders of glycosylation (CDG) are a heterogeneous group of disorders caused by deficient glycosylation, primarily affecting the N-linked pathway. It is estimated that over 40% of CDG patients lack a confirmatory molecular diagnosis. The purpose of this study was to improve molecular diagnosis for CDG by developing and validating a next generation sequencing (NGS) panel for comprehensive mutation detection in 24 genes known to cause CDG.
NGS validation was performed on 12 positive control CDG patients. These samples were blinded as to the disease causing mutations. Both RainDance and Fluidigm platforms were used for sequence enrichment and targeted amplification. The SOLiD platform was used for sequencing the amplified products. Bioinformatic analysis was performed using NextGENe® software.
The disease causing mutations were identified by NGS for all 12 positive controls. Additional variants were also detected in three controls that are known or predicted to impair gene function and may contribute to the clinical phenotype.
We conclude that development of NGS panels in the diagnostic laboratory where multiple genes are implicated in a disorder is more cost-effective and will result in improved and faster patient diagnosis compared with a gene-by-gene approach. Recommendations are also provided for data analysis from the NGS-derived data in the clinical laboratory, which will be important for the widespread use of this technology.
congenital disorders of glycosylation; next generation sequencing; molecular diagnostic testing; target enrichment; bioinformatics
The 22q11.2 deletion syndrome is a common multisystem genomic disorder with congenital and later-onset manifestations, including congenital heart disease, intellectual disability, and psychiatric illness, that may affect long-term functioning. There are limited data on adult functioning in 22q11.2 deletion syndrome.
We used the Vineland Adaptive Behavior Scales to assess functioning in 100 adults with 22q11.2 deletion syndrome (n = 46 male; mean age = 28.8 (standard deviation = 9.7) years) where intellect ranged from average to borderline (n = 57) to mild intellectual disability (n = 43).
More than 75% of the subjects scored in the functional deficit range. Although personal, vocational, and financial demographics confirmed widespread functional impairment, daily living skills and employment were relative strengths. Intelligence quotient was a significant predictor (P < 0.001) of overall and domain-specific adaptive functioning skills. A diagnosis of schizophrenia was a significant predictor (P < 0.05) of overall adaptive functioning, daily living skills, and socialization scores. Notably, congenital heart disease, history of mood/anxiety disorders, sex, and age were not significant predictors of functioning.
Despite functional impairment in adulthood that is primarily mediated by cognitive and psychiatric phenotypes, relative strengths in activities of daily living and employment have important implications for services and long-term planning. These results may help to inform expectations about outcomes for patients with 22q11.2 deletion syndrome.
PMID: 22744446 CAMSID: cams2329
22q11 deletion syndrome; adaptive functioning; heart defects; congenital; intellectual disability; schizophrenia
Genetic research involving human participants can pose challenging questions related to ethical and regulatory standards for research oversight. However, few empirical studies describe how genetic researchers and institutional review board (IRB) professionals conceptualize ethical issues in genetic research or where common ground might exist.
Parallel online surveys collected information from human genetic researchers (n = 351) and IRB professionals (n = 208) regarding their views about human participant oversight for genetic protocols.
A range of opinions were observed within groups on most issues. In both groups, a minority thought it likely that people would be harmed by participation in genetic research or identified from coded genetic data. A majority of both groups agreed that reconsent should be required for four of the six scenarios presented. Statistically significant differences were observed between groups on some issues, with more genetic researcher respondents trusting the confidentiality of coded data, fewer expecting harms from reidentification, and fewer considering reconsent necessary in certain scenarios.
The range of views observed within and between IRB and genetic researcher groups highlights the complexity and unsettled nature of many ethical issues in genome research. Our findings also identify areas where researcher and IRB views diverge and areas of common ground.
comparison; genetics; human genomics; identifiability; institutional review board; reconsent; survey
Appropriate management of autosomal dominant disorders reduces morbidity and mortality, but relies on identifying which family members are affected. Genetic testing may identify relatives needing follow-up, but is underutilized. We conducted this study to identify barriers to genetic testing for one disorder, hereditary hemorrhagic telangiectasia (HHT).
Surveys and on-line discussion groups with people from HHT families.
Multiple barriers to HHT genetic testing were identified including lack of knowledge about genetic testing, problems with access, and emotional barriers. Many participants: did not understand the rationale for HHT testing or benefits of early detection; believed that genetic testing is expensive and not covered by insurance; believed that primary care providers don’t know how to order genetic testing. Access to HHT testing is limited by distance from an HHT Center or a genetics clinic. Emotional barriers include fear of insurance discrimination; denial of having HHT or being at risk; guilt and stigma.
Voluntary disease organizations should develop and disseminate brief educational materials that describe the rationale for genetic testing, and emphasize the benefits of early detection and treatment. In addition, laboratories offering genetic testing should provide support for primary care physicians to order and interpret genetic tests.
Hereditary hemorrhagic telangiectasia; genetic testing; barriers; utilization; on-line discussion
To assess the impact of a multi-modal interdisciplinary course in genetic cancer risk assessment (GCRA) and research collaboration for community-based clinicians. Clinicians are increasingly requested to conduct GCRA, but many are inadequately prepared to provide these services.
A prospective analysis of 131 participants (48 physicians, 41 advanced-practice nurses and 42 genetic counselors) from community settings across the U.S. The course was delivered in three phases: distance didactic learning, face-to-face training and 12 months of Web-based professional development activities to support integration of skills into practice. Cancer genetics knowledge, skills, professional self-efficacy and practice changes were measured at baseline, immediate- and 14-months-post course.
Knowledge, skills and self-efficacy scores were significantly different between practice disciplines; however, post scores increased significantly overall and for each discipline (p<.001). Fourteen-month practice outcomes reflect significant increases in provision of GCRA services (p=.018), dissemination of cancer prevention information (p=.005) and high-risk screening recommendations (p=.004) to patients, patient enrollment in research (p=.013), and educational outreach about GCRA (p=.003).
Results support the efficacy of the multi-modal course as a tool to develop a genetically literate workforce. Sustained alumni participation in Web-based professional development activities has evolved into a distance-mediated Community of Practice in clinical cancer genetics, modeling the lifelong learning goals envisioned by leading CME stakeholders.
Cancer Genetics; Education; Personalized Medicine
To assess the effectiveness of computerized familial risk assessment and tailored messages for identifying individuals for targeted cancer prevention strategies and motivating behavior change.
We conducted a randomized clinical trial in primary care patients aged 35–65 years using Family Healthware, a self-administered, internet-based tool that collects family history for six common diseases including breast cancer, colon cancer, and ovarian cancer, stratifies risk into three tiers, and provides tailored prevention messages. Cancer screening adherence and consultation were measured at baseline and 6-month follow-up.
Of 3283 participants, 34% were at strong or moderate risk of at least one of the cancers. Family Health-ware identified additional participants for whom earlier screening (colon cancer, 4.4%; breast cancer, women ages: 35–39 years, 9%) or genetic assessment (colon cancer, 2.5%; breast cancer, 10%; and ovarian cancer, 4%) may be indicated. Fewer than half were already adherent with risk-based screening. Screening adherence improved for all risk categories with no difference between intervention and control groups. Consultation with specialists did not differ between groups.
Family Healthware identified patients for intensified cancer prevention. Engagement of clinicians and patients, integration with clinical decision support, and inclusion of nonfamilial risk factors may be necessary to achieve the full potential of computerized risk assessment.
family history; risk assessment; early detection of cancer; neoplasms; health knowledge; attitudes; practice
cancer genetics; somatic mutation; genetic susceptibility
Pharmacogenetic (PGx) testing can inform drug dosing and selection by aiding in estimating a patient’s genetic risk of adverse response and/or failure to respond. Some PGx tests may generate ancillary clinical information unrelated to the drug treatment question for which testing is done – an informational “side effect.” We aimed to assess public interest and concerns about PGx tests and ancillary information.
We conducted a random-digit-dial phone survey of a sample of the U.S. public.
We achieved an overall response rate of 42% (n=1,139). When the potential for ancillary information was presented, 85% (±2.82%) of respondents expressed interest in PGx testing, compared to 82% (±3.02%) prior to discussion of ancillary information. Most respondents (89%±2.27%) indicated that physicians should inform patients that a PGx test may reveal ancillary risk information before testing is ordered. Respondents’ interest in actually learning of the ancillary risk finding significantly differed based on disease severity, availability of an intervention, and test validity, even after adjusting for age, gender, education and race.
Under the limited information conditions presented in the survey, the potential of ancillary information does not negatively impact public interest in PGx testing. Interest in learning ancillary information is well-aligned with the public’s desire to be informed about potential benefits and risks prior to testing, promoting patient autonomy.
Autosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined.
We used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia.
We describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology-mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches.
We hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu-specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients.
SPG4; spastin; intragenic rearrangements; exon mutations; FoSTeS
Lynch syndrome accounts for 2–5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases.
Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM1,2,6, MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases.
A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM1,2,6, MMRpredict, and MMRpro were able to distinguish mutation carriers from noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM1,2,6, 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases.
Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients.
endometrial cancer; genetic screening; genetic testing; Lynch syndrome; prediction models