Publications by authors named "Kathleen A Leppig"

38 Publications

Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.

JNCI Cancer Spectr 2021 Aug 8;5(4):pkab044. Epub 2021 May 8.

Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.

Background: Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions.

Methods: We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (, , , , , , and ) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results.

Results: Out of the 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure.

Conclusions: Our study provides population-based penetrance estimates for the understudied genes , , and and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve health care through early diagnosis and preventative screening.
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http://dx.doi.org/10.1093/jncics/pkab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346699PMC
August 2021

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening.

J Pers Med 2021 Jun 10;11(6). Epub 2021 Jun 10.

Kaiser Permanente Washington, Seattle, WA 98101, USA.

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches.
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http://dx.doi.org/10.3390/jpm11060538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230217PMC
June 2021

Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder.

Otol Neurotol 2021 09;42(8):e1143-e1151

Virginia Merrill Bloedel Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington.

Objectives: To better distinguish NOG-related-symphalangism spectrum disorder (NOG-SSD) from chromosomal 17q22 microdeletion syndromes and to inform surgical considerations in stapes surgery for patients with NOG-SSD.

Background: Mutations in NOG cause a variety of skeletal syndromes that often include conductive hearing loss. Several microdeletions of chromosome 17q22 lead to severe syndromes with clinical characteristics that overlap NOG-SSD. Isolated deletion of NOG has not been described, and therefore the contribution of NOG deletion in these syndromes is unknown.

Methods: Two families with autosomal dominant NOG-SSD exhibited stapes ankylosis, facial dysmorphisms, and skeletal and joint anomalies. In each family, NOG was evaluated by genomic sequencing and candidate mutations confirmed as damaging by in vitro assays. Temporal bone histology of a patient with NOG-SSD was compared with temporal bones of 40 patients diagnosed with otosclerosis.

Results: Family 1 harbors a 555 kb chromosomal deletion encompassing only NOG and ANKFN1. Family 2 harbors a missense mutation in NOG leading to absence of noggin protein. The incus-footplate distance of the temporal bone was significantly longer in a patient with NOG-SSD than in patients with otosclerosis.

Conclusion: The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions. Severe clinical findings in other microdeletion cases are likely due to deletion of genes other than NOG. Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis.
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http://dx.doi.org/10.1097/MAO.0000000000003176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486042PMC
September 2021

Preferences of biobank participants for receiving actionable genomic test results: results of a recontacting study.

Genet Med 2021 06 18;23(6):1163-1166. Epub 2021 Feb 18.

Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA, USA.

Purpose: We sought to determine preferences of biobank participants whose samples were tested for clinically actionable variants but did not respond to an initial invitation to receive results.

Methods: We recontacted a subsample of participants in the Kaiser Permanente Washington/University of Washington site of the Electronic Medical Records and Genomics (eMERGE3) Network. The subsample had provided broad consent for their samples to be used for research but had not responded to one initial mailed invitation to receive their results. We sent a letter from the principal investigators with phone outreach. If no contact was made, we sent a certified letter stating our assumption that participant had actively refused. We collected reasons for declining.

Results: We recontacted 123 participants. Response rate was 70.7% (n = 87). Of these, 62 (71.3%) declined the offer of returned results and 25 (28.7%) consented. The most common reasons provided for refusal included not wanting to know (n = 22) and concerns about insurability (n = 28).

Conclusion: Efforts to recontact biobank participants can yield high response. Though active refusal upon recontact was common, our data do not support assuming initial nonresponse to be refusal. Future research can work toward best practices for reconsenting, especially when clinically actionable results are possible.
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http://dx.doi.org/10.1038/s41436-021-01111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194390PMC
June 2021

DLG4-related synaptopathy: a new rare brain disorder.

Genet Med 2021 05 17;23(5):888-899. Epub 2021 Feb 17.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
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http://dx.doi.org/10.1038/s41436-020-01075-9DOI Listing
May 2021

The FamilyTalk randomized controlled trial: patient-reported outcomes in clinical genetic sequencing for colorectal cancer.

Cancer Causes Control 2021 May 16;32(5):483-492. Epub 2021 Feb 16.

Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA, USA.

As genetics gains favor in clinical oncology, it is important to address patient concerns around confidentiality, privacy, and security of genetic information that might otherwise limit its utilization. We designed a randomized controlled trial to assess the social impact of an online educational tool (FamilyTalk) to increase family communication about colorectal cancer (CRC) risk and screening. Of 208 randomized participants, 149 (71.6%) returned six-month surveys. Overall, there was no difference in CRC screening between the study arms. Privacy and confidentiality concerns about medical and genetic information, reactions to genetic test results, and lifestyle changes did not differ between arms. Participants with pathogenic or likely pathogenic (P/LP) and variant of uncertain significance (VUS) results were more likely than those with negative results to report that the results accurately predicted their disease risks (OR 5.37, p = 0.02 and OR 3.13, p = 0.02, respectively). This trial demonstrated no evidence that FamilyTalk impacted patient-reported outcomes. Low power, due to the limited number of participants with P/LP results in the overall sample, as well as the short follow-up period, could have contributed to the null findings.
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http://dx.doi.org/10.1007/s10552-021-01398-1DOI Listing
May 2021

Characteristics Associated with Participation in ENGAGED 2 - A Web-based Breast Cancer Risk Communication and Decision Support Trial.

Perm J 2020 12;24:1-4

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.

Purpose: We evaluated demographic and clinical characteristics associated with participation in a clinical trial testing the efficacy of an online tool to support breast cancer risk communication and decision support for risk mitigation to determine the generalizability of trial results.

Methods: Eligible women were members of Kaiser Permanente Washington aged 40-69 years with a recent normal screening mammogram, heterogeneously or extremely dense breasts and a calculated risk of > 1.67% based on the Breast Cancer Surveillance Consortium 5-year breast cancer risk model. Trial outcomes were chemoprevention and breast magnetic resonance imaging by 12-months post-baseline. Women were recruited via mail with phone follow-up using plain language materials notifying them of their density status and higher than average breast cancer risk. Multivariable logistic regression calculated independent odds ratios (ORs) for associations between demographic and clinical characteristics with trial participation.

Results: Of 2,569 eligible women contacted, 995 (38.7%) participated. Women with some college (OR = 1.99, 95% confidence interval [CI] 1.34-2.96) or college degree (OR = 3.35, 95% CI 2.29-4.90) were more likely to participate than high school-educated women. Race/ethnicity also was associated with participation (African-American OR = 0.50, 95% CI 0.29-0.87; Asian OR = 0.22, 95% CI 0.12-0.41). Multivariate adjusted ORs for family history of breast/ovarian cancer were not associated with trial participation.

Discussion: Use of plain language and potential access to a website providing personal breast cancer risk information and education were insufficient in achieving representative participation in a breast cancer prevention trial. Additional methods of targeting and tailoring, potentially facilitated by clinical and community outreach, are needed to facilitate equitable engagement for all women.
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http://dx.doi.org/10.7812/TPP/19.205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849258PMC
December 2020

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.

Genet Med 2021 04 10;23(4):653-660. Epub 2020 Dec 10.

Institute of Child Health, University Collge London, London, UK.

Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."
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http://dx.doi.org/10.1038/s41436-020-01020-wDOI Listing
April 2021

Participant choices for return of genomic results in the eMERGE Network.

Genet Med 2020 11 16;22(11):1821-1829. Epub 2020 Jul 16.

Divisions of Human Genetics and Patient Services, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Purpose: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium.

Methods: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices.

Results: Across the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes.

Conclusion: Offering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.
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http://dx.doi.org/10.1038/s41436-020-0905-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477450PMC
November 2020

Ethical conflicts in translational genetic research: lessons learned from the eMERGE-III experience.

Genet Med 2020 10 18;22(10):1667-1672. Epub 2020 Jun 18.

Center for Biomedical Ethics and Society, Vanderbilt University Medical Center, Nashville, TN, USA.

Purpose: The Electronic Medical Records and Genomics (eMERGE) Consortium integrated biorepository-based research with electronic health records (EHR) to return results from large-scale genetic tests to participants and uploaded those data into the EHR. This article explores the ethical issues investigators encountered in that process.

Methods: We conducted in-depth, semistructured interviews with study personnel of the eMERGE-III Consortium sites that returned results.

Results: We discuss major ethical issues that arose while attempting to return research results from the eMERGE Consortium to individual participants. These included difficulties recontacting those participants who had not explicitly consented to such and disclosing results to many participants with insufficient infrastructure and staff. Investigators reported being driven by a supererogatory clinical impulse.

Conclusion: All these issues ultimately derive from ethical conflicts inherent to translational work being done at the interface of research and clinical care. A critical rethinking of this divide is important, but infrastructural support for such work is necessary for an ethically sound rollout of large-scale genetic testing.
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http://dx.doi.org/10.1038/s41436-020-0863-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521988PMC
October 2020

Understanding the Return of Genomic Sequencing Results Process: Content Review of Participant Summary Letters in the eMERGE Research Network.

J Pers Med 2020 May 13;10(2). Epub 2020 May 13.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.
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http://dx.doi.org/10.3390/jpm10020038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354464PMC
May 2020

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

J Pers Med 2020 Apr 27;10(2). Epub 2020 Apr 27.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.
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http://dx.doi.org/10.3390/jpm10020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354592PMC
April 2020

Redefining the Etiologic Landscape of Cerebellar Malformations.

Am J Hum Genet 2019 09 29;105(3):606-615. Epub 2019 Aug 29.

Genetic Services, Kaiser Permanente Washington, Seattle, WA 98112, USA.

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731369PMC
September 2019

"It would be so much easier": health system-led genetic risk notification-feasibility and acceptability of cascade screening in an integrated system.

J Community Genet 2019 Oct 6;10(4):461-470. Epub 2019 Mar 6.

Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.

Assess the feasibility and acceptability of health system-led genetic risk notification in a US integrated health system. We conducted semi-structured phone interviews with individuals age 40-64 years who had undergone genetic sequencing, but had not yet received their results, assessing attitudes to direct outreach to relatives. During each interview, we collected contact information for adult relatives identified as members of the same system and attempted to identify each relative in administrative data. We conducted 20 interviews. Most participants expressed support for Kaiser Permanente Washington involvement in familial risk notification. Direct outreach to relatives received the most unqualified support; outreach to the relatives' physician or interaction with the relatives' electronic medical record received more tempered support. Support was motivated by the desire to have risk communicated accurately and quickly. The most common caveat was a desire to alert relatives before the health system contacted them. Of 57 named relatives who were members of the same health system, we retrieved a single match for 40 (70.2%) based on name or birthdate. Health system involvement in familial risk notification received support in a sample of patients in a US integrated health system, and identification of relatives is feasible.
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http://dx.doi.org/10.1007/s12687-019-00412-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754469PMC
October 2019

Trends in BRCA Test Utilization in an Integrated Health System, 2005-2015.

J Natl Cancer Inst 2019 08;111(8):795-802

See the Notes section for the authors' affiliations.

Background: Genetic testing to determine BRCA status has been available for over two decades, but there are few population-based studies of test diffusion. We report 10-year trends in BRCAtesting in an integrated health-care system with long-standing access to genetic services.

Methods: A cohort of women aged 18 years and older was created to ascertain BRCA testing (n = 295 087). Annual testing rates between 2005 and 2015 were calculated in all women with and without incident (ie, newly diagnosed) breast and ovarian cancers and in clinically eligible subgroups by family cancer history, personal cancer history, and age at diagnosis. Secular trends were assessed using Poisson regression. Women tested early (2005-2008), midway (2009-2012), and late (2013-2015) in the study period were compared in cross-sectional analyses.

Results: Between 2005 and 2015, annual testing rates increased from 0.6/1000 person-years (pys) (95% confidence interval [CI] = 0.4 to 0.7/1000 pys) to 0.8/1000 pys (95% CI = 0.6 to 1.0/1000 pys) in women without incident breast or ovarian cancers. Rates decreased from 71.5/1000 pys (95% CI = 42.4 to 120.8/1000 pys) to 44.4/1000 pys (95% CI = 35.5 to 55.6/1000 pys) in women with incident diagnoses, despite improvements in provision of timely BRCA testing during this time frame. We found no evidence of secular trends in clinically eligible subgroups including women with family history indicating increased hereditary cancer risk, but no personal cancer history. At the end of the study period, 97.0% (95% CI = 96.6% to 97.3%) of these women remained untested.

Conclusion: Many eligible women did not receive BRCA testing despite having insurance coverage and access to specialty genetic services, underscoring challenges to primary and secondary hereditary cancer prevention.
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http://dx.doi.org/10.1093/jnci/djz008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695306PMC
August 2019

Development of FamilyTalk: an Intervention to Support Communication and Educate Families About Colorectal Cancer Risk.

J Cancer Educ 2020 06;35(3):470-478

Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.

IFamily members of individuals with colorectal cancer (CRC) may be at increased risk of developing the disease. However, the majority of CRC can be prevented through colonoscopy screening and family members may not be aware if they are recommended to pursue earlier screening because of their family history of CRC. As such, tools must be developed to effectively communicate potential changes to the recommended age for colonoscopy screening and other important CRC-related information to family members. We modified and adapted a successful intervention for families with melanoma to be appropriate for families with CRC to increase communication and screening in family members. The multistep process included the following: (1) developing a paper version of the intervention, (2) piloting the paper version among families with CRC, (3) developing the web-based version, and (4) testing the intervention for usability. Qualitative data was collected and analyzed for pilot testing. Usability testing utilized both qualitative and quantitative data. Patients with CRC liked the paper version and had multiple suggestions, including adding a better introduction, sections on genetics and family history, and clearer communication assistance. The web-based tool was well received and improved upon the linear book format with links, better section instructions, and more proactive communication tools for families. These processes produced materials that satisfied individuals from various families with assistance and support for communicating about CRC. Evaluating the effects of the tools in rigorous research projects is the next step.
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http://dx.doi.org/10.1007/s13187-019-1484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688969PMC
June 2020

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

Harmonizing Outcomes for Genomic Medicine: Comparison of eMERGE Outcomes to ClinGen Outcome/Intervention Pairs.

Healthcare (Basel) 2018 Jul 13;6(3). Epub 2018 Jul 13.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

Genomic medicine is moving from research to the clinic. There is a lack of evidence about the impact of genomic medicine interventions on health outcomes. This is due in part to a lack of standardized outcome measures that can be used across different programs to evaluate the impact of interventions targeted to specific genetic conditions. The eMERGE Outcomes working group (OWG) developed measures to collect information on outcomes following the return of genomic results to participants for several genetic disorders. These outcomes were compared to outcome intervention pairs for genetic disorders developed independently by the ClinGen Actionability working group (AWG). In general, there was concordance between the defined outcomes between the two groups. The ClinGen outcomes tended to be from a higher level and the AWG scored outcomes represented a subset of outcomes referenced in the accompanying AWG evidence review. eMERGE OWG outcomes were more detailed and discrete, facilitating a collection of relevant information from the health records. This paper demonstrates that common outcomes for genomic medicine interventions can be identified. Further work is needed to standardize outcomes across genomic medicine implementation projects and to make these publicly available to enhance dissemination and assist in making precision public health a reality.
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http://dx.doi.org/10.3390/healthcare6030083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164315PMC
July 2018

Collaborations in medical genetics: 10-Year history of an ongoing Vietnamese-North American Collaboration.

Mol Genet Genomic Med 2018 03;6(2):129-133

Genetic Services, Kaiser Permanente of Washington, Seattle, WA, USA.

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http://dx.doi.org/10.1002/mgg3.383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902404PMC
March 2018

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

Genet Med 2018 10 22;20(10):1175-1185. Epub 2018 Feb 22.

National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

Purpose: To characterize the molecular genetics of autosomal recessive Noonan syndrome.

Methods: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.

Results: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.

Conclusion: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
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http://dx.doi.org/10.1038/gim.2017.249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105555PMC
October 2018

A Report on Ten Asia Pacific Countries on Current Status and Future Directions of the Genetic Counseling Profession: The Establishment of the Professional Society of Genetic Counselors in Asia.

J Genet Couns 2018 02 11;27(1):21-32. Epub 2017 Jul 11.

Department of Pediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

The Professional Society of Genetic Counselors in Asia (PSGCA) was recently established as a special interest group of the Asia Pacific Society of Human Genetics. Fostering partnerships across the globe, the PSGCA's vision is to be the lead organization that advances and mainstreams the genetic counseling profession in Asia and ensures individuals have access to genetic counseling services. Its mission is to promote quality genetic counseling services in the region by enhancing practice and curricular standards, research and continuing education. The PSGCA was formally launched during the Genetic Counseling Pre-Conference Workshop held at the 11th Asia-Pacific Conference on Human Genetics in Hanoi, Viet Nam, September 16, 2015. The pre-conference workshop provided an opportunity for medical geneticists and genetic counselors from across 10 Asia Pacific countries to learn about the varied genetic counseling practices and strategies for genetic counseling training. This paper provides an overview of the current status and challenges in these countries, and proposed course of unified actions for the future of the genetic counseling profession.
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http://dx.doi.org/10.1007/s10897-017-0115-6DOI Listing
February 2018

Identifying opportunities for collaboration and growth of genetic counseling services in the Asia Region.

J Community Genet 2017 Jul 25;8(3):243-248. Epub 2017 May 25.

Group Health Cooperative, Seattle, WA, USA.

The Genetic Counseling Pre-Conference Workshop (GCPCW) was held on September 16, 2015, in Hanoi, Vietnam. We report the GCPCW outcomes obtained from pre- and post-conference questionnaires, case-review breakout session, and an open discussion of needs for genetic counseling services in the Asia region. The GCPCW participants completed questionnaires with closed- and open-ended questions regarding the status and needs of providing genetic counseling services in Asia. Utilizing thematic content analysis, common themes shared during the case-review breakout session are summarized and survey results are tabulated. Of the 71 participants, pre- and post-conference questionnaires were returned by 57 (80%) and 44 (62%) individuals, respectively. Of the 42 participants who did not identify themselves as students in training, 36 (86%) stated they are currently providing genetic counseling services. Participants cited that the most useful information obtained during the GCPCW related to the status of genetic counseling services in the region, discovery of shared challenges, professional networking, and the need to establish genetic counseling training programs and its accreditation. The GCPCW provided a collaborative forum to address current challenges and needs of genetic counseling services in the region. Strategies were identified to foster genetic counseling training and clinical service opportunities.
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http://dx.doi.org/10.1007/s12687-017-0307-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496845PMC
July 2017

Building a family network from genetic testing.

Mol Genet Genomic Med 2017 Mar 29;5(2):122-129. Epub 2016 Dec 29.

Department of Medicine (Medical Genetics) and Genomic Sciences University of Washington Seattle WA 98195 USA.

Background: Genetic testing has multigenerational and familial repercussions. However, the "trickle-down effect" of providing genetic counseling and testing to family members at risk after an initial identification of a pathogenic variant in a medically actionable gene has been poorly understood.

Methods: Three probands were identified during the pharmacogenetics research phase of eMERGEII (electronic MEdical Record and Genomics, phase II) to have variants in genes associated with autosomal dominant adult-onset disorders determined to be actionable by the American College of Medical Genetics (ACMG). Two of the three probands had variants that were classified as pathogenic and the third proband had a variant ultimately classified of uncertain significance, but of concern due to the proband's own phenotype. All probands had additional family members at risk for inheriting the variant. Two of the three probands had family members who received their medical care from the same health care system, Group Health Cooperative (GHC). It was recommended that the proband contact their family members at risk to be referred to genetic counseling for consideration of genetic testing.

Results: The two probands with pathogenic variants contacted some of their family members at risk. Individuals contacted included children and adult grandchildren, particularly if they received their medical care at GHC. To the best of our knowledge, siblings and more distant relatives at risk were not informed by the proband of their genetic risk.

Conclusions: Establishing a family network is essential to disseminate knowledge of genetic risk. These three initial cases describe our experience of contacting eMERGE participants with identified variants, providing the probands with appropriate genetic counseling and care coordination, and recommendations for contacting family members at risk. Greater challenges were observed for coordinating genetics care for family members and extending the family network to include other relatives at risk.
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http://dx.doi.org/10.1002/mgg3.259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370219PMC
March 2017

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Genome Res 2015 Mar 30;25(3):305-15. Epub 2015 Jan 30.

Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
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http://dx.doi.org/10.1101/gr.183483.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352885PMC
March 2015

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

Genet Med 2014 Sep 6;16(9):711-6. Epub 2014 Mar 6.

Department of Dermatology, Mayo Clinic, Jacksonville, Florida, USA.

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.
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http://dx.doi.org/10.1038/gim.2014.19DOI Listing
September 2014

Phenotypic and molecular characterization of 19q12q13.1 deletions: a report of five patients.

Am J Med Genet A 2014 Jan 15;164A(1):62-9. Epub 2013 Nov 15.

Providence Sacred Heart Medical Center, Molecular Diagnostics, Spokane, Washington.

A syndrome associated with 19q13.11 microdeletions has been proposed based on seven previous cases that displayed developmental delay, intellectual disability, speech disturbances, pre- and post-natal growth retardation, microcephaly, ectodermal dysplasia, and genital malformations in males. A 324-kb critical region was previously identified as the smallest region of overlap (SRO) for this syndrome. To further characterize this microdeletion syndrome, we present five patients with deletions within 19q12q13.12 identified using a whole-genome oligonucleotide microarray. Patients 1 and 2 possess deletions overlapping the SRO, and Patients 3-5 have deletions proximal to the SRO. Patients 1 and 2 share significant phenotypic overlap with previously reported cases, providing further definition of the 19q13.11 microdeletion syndrome phenotype, including the first presentation of ectrodactyly in the syndrome. Patients 3-5, whose features include developmental delay, growth retardation, and feeding problems, support the presence of dosage-sensitive genes outside the SRO that may contribute to the abnormal phenotypes observed in this syndrome. Multiple genotype-phenotype correlations outside the SRO are explored, including further validation of the deletion of WTIP as a candidate for male hypospadias observed in this syndrome. We postulate that unique patient-specific deletions within 19q12q13.1 may explain the phenotypic variability observed in this emerging contiguous gene deletion syndrome.
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http://dx.doi.org/10.1002/ajmg.a.36201DOI Listing
January 2014

Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network.

Genet Med 2012 Apr 23;14(4):424-31. Epub 2012 Feb 23.

University of Washington, Seattle, Washington, USA.

Purpose: Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.

Methods: The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making.

Results: Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).

Conclusion: The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.
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http://dx.doi.org/10.1038/gim.2012.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723451PMC
April 2012

EXT2-positive multiple hereditary osteochondromas with some features suggestive of metachondromatosis.

Skeletal Radiol 2012 May 4;41(5):607-10. Epub 2011 Sep 4.

Orthopaedics and Sports Medicine, Seattle Children's Hospital, 4800 Sandpoint Way NE, Seattle, WA 98105, USA.

Metachondromatosis (MC) and hereditary multiple osteochondromas (HMO) are thought to be distinct disorders, each with characteristic x-ray and clinical features. Radiographic differences are the current mainstay of differential diagnosis. Both disorders are autosomal dominant, but the majority of patients with HMO have mutations in EXT-1 or EXT 2 genes. The genetic defect in MC is unknown, although recent studies indicate a possible identifiable mutation. The cancer risk in HMO is thought to be greater than in MC, although the small number of cases make such conjecture imprecise. The purpose of this report is to review existing literature and examine whether radiographic findings in HMO and MC can be reliable as a stand-alone means of differential diagnosis. Three members of a multi-generational family with an autosomal dominant exostosis syndrome were studied by clinical examination and complete skeletal survey. The roentgenographic characteristics of all osteochondromas were analyzed. The father underwent gene sequencing for EXT-1 and EXT-2, which revealed a novel EXT-2 mutation. Typical radiographic and clinical findings of both HMO and MC were seen throughout the family as well as in individuals. These family study findings contradict many of the long-standing clinical and x-ray diagnostic criteria for differentiating MC from HMO. The phenotypic crossover between the two conditions in this family, and results of genetic analysis, suggest that in the absence of a definitive genetic diagnosis, radiographic and clinical diagnosis of past and future cases HMO and MC may not be as reliable as previously assumed.
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http://dx.doi.org/10.1007/s00256-011-1261-9DOI Listing
May 2012
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