Advanced Roles in Research and Advocacy: Genetic Counseling in Cystic Fibrosis and Angelman Syndrome

Career Path and Early Research in Cystic Fibrosis

Karen, a research genetic counselor at Johns Hopkins University, began her journey into the medical field as a child interested in books by Luline McDaniel, which focused on pediatric cancer and cystic fibrosis (CF). This early interest led her to major in biology at a small liberal arts college. While in college, she met a student with cystic fibrosis whose neighbor worked at Case Western Reserve University. This connection facilitated a summer internship in the lab of researcher Mitch Drum.

During this internship between her junior and senior years, Karen conducted wet bench basic laboratory work investigating CFTR promoter variants. This experience was pivotal; while she initially intended to pursue a PhD in genetics, the summer in the lab convinced her that she did not want a career in laboratory research. Consequently, she pivoted toward genetic counseling after meeting a counselor in the same lab who was pursuing a PhD. Karen earned her degree in genetic counseling from the University of Maryland and then received a Fulbright scholarship to live in Dublin, Ireland. In Dublin, she worked in an adult cystic fibrosis clinic, conducting a study to determine if knowledge, attitudes, and education regarding CF correlated with patient outcomes. The result of this specific study indicated there was no such correlation.

Upon returning to the United States, Karen sought a clinical role to prepare for her board exams. She worked as a pediatric genetic counselor at Nationwide Children's Hospital in Columbus, Ohio for nearly two years. While she participated in specialty clinics, including CF, her involvement was limited because the CF newborn screening follow-up was managed by another counselor. In 2011, through a series of coincidences, she joined Johns Hopkins University to work on the CFTR2 project under Gary Cutting in the Cutting Lab. She has remained at Hopkins for nearly 15 years in a fully research-based role as a genetic counselor with no clinical components.

The CFTR2 Project and Data Curation

The Clinical and Functional Translation of CFTR (CFTR2) project is an international initiative aimed at interpreting every CFTR variant reported in individuals with cystic fibrosis. The primary goal is to make this information freely accessible to clinicians, researchers, and patients via a public website. Currently, the dataset includes over $123,000$ individuals with CF from $56$ countries, regions, and territories. Through this initiative, the team has interpreted nearly $1,400$ unique CFTR variants, covering over $98\%$ of the people in the dataset for whom both reported CFTR alleles are known.

Karen's primary responsibilities within CFTR2 include maintaining relationships with data providers, such as the United States CF Foundation (CFF), the European Cystic Fibrosis Society (ECFS), CF Canada, and the UK CF Trust. She actively gathers, maintains, and analyzes data from these registries. Additionally, she writes the patient-facing language for the website. This role utilizes various genetic counseling skills, including clinical data curation, variant interpretation, and both patient and provider education.

CF Genetics Education and Q&A Service

In response to a community need for specialized information, Karen established the CF Genetics Education and Q&A Service. When the CFTR2 website launched, it provided not only variant interpretations but also clinical data and functional testing results. This prompted a surge in questions from patients who found that their local clinics could not provide technical answers regarding mutation mechanisms. Although Karen maintains that she is not a specific patient's counselor, the team recognized a role for providing genetics education.

Since 2012, the service has tracked over $2,700$ inquiries. In 2017, the education response was formalized as a grant line item. Approximately one-third of the questions involve variants not currently interpreted or available on the website. Another $15\%$ of inquiries focus on the R117H variant or the poly-T tract ($5T$, $7T$, $9T$), which are technically complex regions of the CFTR gene. Interestingly, the audience is split, with $40\%$ of questions coming from genetic counselors and $40\%$ from CF clinicians or researchers. Karen must tailor her communication to bridge the gap between bench research and clinical care, providing nuanced explanations for rare or ambiguous cases.

Translational Research and Lab Collaboration

While Karen does not perform laboratory work herself, she collaborates closely with the Cutting Lab at Hopkins. The lab's work involves characterizing CFTR variants to determine their effects on protein production and function using cell-based systems. They also test drug responses to CFTR modulators, which are genotype-specific therapies. This research is critical for determining if a patient with a rare variant will respond to available medications.

Karen serves as the human bridge for this research, translating laboratory findings into plain language for families and referring providers. An example of this impact involved two boys with a rare CFTR variant ($Q359R$) who were not initially eligible for modulator treatment. Nasal brushing was performed to collect primary cells, which were drug-tested in the lab. The results showed the variant was likely to respond to Ivacaftor ($\text{Kalydeco}$). This data enabled the family to secure off-label insurance coverage for the drug, resulting in a significant clinical improvement (e.g., disappearance of a chronic cough).

The Impact Project and Telehealth Access

A recent development in Karen's career is her role as Principal Investigator (PI) for the Impact Project, which aims to improve access to CF-specific genetic counseling via telehealth. This project is funded by the CF Foundation and involves partnerships with Northwell Health and Brigham and Women’s Hospital. The project addresses a gap in care: most CF centers do not have an institutional genetic counselor with specific CFTR expertise, leading to inequitable access to counseling.

To address this, the project partnered with the Genetic Support Foundation (GSF), a non-profit telehealth organization. Karen and her colleagues developed a specialized CF training curriculum for GSF counselors. Currently, $10$ genetic counselors have completed the training, and $11$ CF centers across $8$ states are participating in a phased rollout. This centralized model serves as a potential blueprint for other rare diseases where specialized knowledge is concentrated in a few locations.

Challenges of Nontraditional Research Roles

Despite the success of her projects, Karen faces several professional challenges. There is no defined path or specialized training for research genetic counselors at her institution. At Johns Hopkins, a clinical career ladder (levels 1-4) exists, but research counselors are excluded from it. To find a structured advancement path, Karen eventually secured a faculty appointment in 2023. Other challenges include "scope creep"—the difficulty of setting boundaries when a role spans research, education, and advocacy. Additionally, in the academic setting, the lack of a doctorate (PhD) can make it harder to establish credibility and authority in research spaces. Finally, she notes the "infinite" nature of research; every project generates numerous spinoff questions, making it difficult to feel a sense of completion.

Angelman Syndrome Overview and FAST

Nikki Armstrong, Vice President of Genetic Services and Education at the Foundation for Angelman Syndrome Therapeutics (FAST), provides a comprehensive overview of Angelman syndrome (AS). AS is a single-gene disorder caused by a lack of functional UBE3A protein in the brain neurons. The incidence is approximately $1$ in $15,000$, though data for older adults is sparse. Typical diagnosis occurs between $12$ and $24$ months, though some subtypes may not be diagnosed until age $5$ to $8$.

Clinical features of AS include a characteristically happy demeanor with frequent laughter, significant impairment in verbal communication (often requiring augmentative communication), gross motor delays, and ataxia. Most individuals require $24/7$ lifelong care. Sleep issues are common, and there is a high frequency of seizures. Currently, there are no approved disease-modifying therapies, though three programs are entering Phase 3 clinical trials, and an AAV gene therapy is in development.

Genetic Mechanisms of Angelman Syndrome

The UBE3A gene is located on chromosome $15$ ($15q11-13$) and is imprinted; the paternal copy is silenced in brain neurons, meaning only the maternal copy is functional. There are four primary genetic mechanisms, often called "genotypes" in the community. Deletions on the maternal chromosome account for $70-80\%$ of cases and are generally the most severe, often involving $10$ to $12$ other deleted genes. UBE3A mutations (pathogenic variants) account for the next group; these can be missense or frameshift and may be inherited from a carrier mother in up to $30\%$ of cases. Paternal Uniparental Disomy (UPD), where both copies of chromosome $15$ are paternal, accounts for $5\%$. Imprinting Center Defects (ICD) account for $3\%$. Mosaicism is also recognized as its own phenotypic group due to its typically less severe presentation.

FAST is the largest non-governmental funder of AS research, having invested over $\$64,000,000$. They focus on five pillars: replacing UBE3A, activating the paternal copy, targeting downstream pathways, addressing other genes in deletion, and preparing for clinical trials. They developed the ORCA (Obtaining Reports on Communication of Individuals with Angelman Syndrome) measure to evaluate communication progress in patients.

Genetic Counseling within Patient Advocacy

Nikki's role at FAST is unique as she provides free, telehealth-based genetic counseling to families in the United States. She maintains licensure across multiple states and carries liability insurance specifically for this purpose. Because she "lives in the disorder," she provides deeper expertise than a generalist counselor might. Her sessions are flexible, often lasting an hour or occurring over multiple days, and focus on interpreting test reports, discussing recurrence risks, and explaining clinical trial options.

Working for a patient advocacy organization (PAO) involves significant project management and liaison work. Nikki reviews industry consent forms, helps craft community letters and press releases, and provides healthcare provider (HCP) education. However, she faces challenges such as being outside the standard medical record system (no access to Epic), lacking a built-in support team like social workers, and managing the costs associated with licensure and CEUs. She also navigates "fuzzy boundaries" between her role as a professional counselor and the PAO's perspective of families as community members and potential donors.

Questions & Discussion

During the Q&A session, an audience member noted the challenge of maintaining boundaries in an organization where the mission is to "cure" a condition that remains uncured. Nikki agreed, noting that while she uses professional contracting at the start of her sessions, there is community pushback regarding the word "cure," which carries deep emotional weight and frustration after years of research without a definitive cure. She emphasized the role of education in explaining the complexities of the drug development process to manage expectations.

A discussion also touched on the creation of education materials for complex genetic concepts, such as the R117H variant in CF. Karen noted that specialized knowledge services are essential because parents of children with rare diseases often become highly expert and require technical, high-level information that general clinics may not be prepared to provide. Both speakers emphasized that genetic counseling skills are highly transferable into research coordination, policy writing, and industry liaison roles, regardless of whether a counselor has a PhD or a traditional clinical role.

Final Self-Review Checklist

1. Proper Nouns: Mitchel Drum, Gary Cutting, Case Western Reserve University, Johns Hopkins, Nationwide Children's Hospital, CFTR2, FAST, ASF, GSF, PPMD, Ivacaftor, Kalydeco, ORCA, Luline McDaniel.

2. Numerical Values: $123,000$ individuals, $56$ countries, $1,400$ variants, $98\%$ coverage, $2,700$ inquiries, $15\%$ R117H, $1$ in $15,000$ AS incidence, $\$64,000,000$ investment.

3. Dialogue/Q&A: Captured boundary challenges and the "cure" terminology frustration.

4. Formatting: Included descriptive headings and paragraphs with blank line separators. LaTeX used for all numeric values and scientific notation.

5. No comments or control tokens are present within the JSON fields.