CSER: Clinical Implementation of Carrier Testing Using NGS (NextGen)

We will investigate the clinical implementation of genome sequencing (GS) for carrier screening to aid reproductive decision-making in adults. The study is organized into three inter-related Projects. The study population will include women and their partners who receive pre-conception testing. In Project 1, we will conduct a Randomized Clinical Trial to test clinical implementation of WGS compared with usual care. We will integrate WGS results with the electronic medical record (EMR), and measure outcomes from patient and physician perspectives. In Project 2, we will perform whole genome sequencing, including validation and interpretation of the identified variants to identify "actionable variants", meaning variants deemed worthy of reporting. This will include a robust approach using a Return of Results Committee (RORC) for determination of reportable results. In Project 3, we will evaluate the ethical and psychosocial implications of expanded carrier screening using WGS for the return of carrier status and secondary findings, and measure the impact on downstream healthcare utilization and cost. Two groups of women are identified through the electronic medical record. The first group has a clinical carrier screening test, usually Cystic Fibrosis (CF), ordered and completed as part of a preconception planning visit. The second group has a carrier screening test, usually CF, performed during pregnancy, they have delivered their baby and are planning a future pregnancy. Eligible women are randomized to either usual care or genome sequencing (GS). Women randomized into the usual care arm have already received their clinical genetic test. These women will not receive genome sequencing. Women in the GS arm will receive their carrier status results for about 700 gene/condition pairs approximately three months after randomization. If there are results to return, women come in for a genetic counseling session. If there are no results, a letter is sent in the mail. Incidental findings (IF) are returned about one month later. As with the carrier status results, all IF are returned in person, and if there are no results a letter is sent in the mail. If a participant is found to be a carrier of an autosomal recessive condition, her male partner is then eligible and invited to participate in the study and receive GS. ]]>
Women eligible for inclusion have a genetic test for carrier status performed prior to or during pregnancy, are current health plan members, are not currently pregnant, are 21-50, have access to email, speak English, and are planning future pregnancies. Women are excluded if their genetic test was for diagnostic purposes, if they are currently pregnant, or if they do not plan on having future children. Male partners are eligible if their enrolled female partner is found to be a carrier of an autosomal recessive genetic condition. ]]>
For all couples considering pregnancy in the United States, professional guidelines recommend offering carrier screening for Cystic Fibrosis (CF). Other limited carrier screening is recommended for specific situations that confer an increased risk, such as Tay Sachs for individuals with Ashkenazi Jewish ancestry. Additionally, carrier screening is typically offered to family members of an identified carrier or affected individual and members of ethnic or racial groups known to have a higher prevalence of a condition. While CF is one of the most common genetic disorders, there are many thousands of autosomal recessive, x-linked, and mitochondrial disease variants that could impact a future pregnancy. Commercially available panels incorporate 10's or a couple hundred conditions, but they are not widely utilized and the testing is limited to well known variants in the genes examined. Carrier screening using genome sequencing could identify more mutations than panel screening and, as a result, identify more couples at risk of bearing children affected by genetic conditions. Carrier testing represents a high proportion of care that is delivered in medical genetics. Thus, this program can be immediately translated to a large number of patients at the end of the study. Further, carrier status is potentially relevant whenever WGS is used in adults of reproductive age, regardless of why the sequencing was ordered. This study's focus on individuals with a near-term interest in learning their carrier status will allow us to rapidly assess the potential impact and outcomes of using WGS for carrier status. Our access to real world patients and clinical settings will make our research broadly generalizable. The comprehensive medical care that is delivered in a managed care setting will enable us to maximize the potential relevance of the genomic data to the patient and to investigate novel data on the program's impact from evaluation of downstream health care utilization and costs.]]>