Genetics and Primary Care: Raising Awareness and Enhancing Cooperation

Abstract

The rapid evolution of the field of genetics in the past several years has opened new opportunities for diagnosis of treatment of genetic disorders. However, the limited availability of medical geneticists has led to difficulty in meeting this evolving need. Integrating awareness of genetic disorders and genetic screening into primary care may facilitate early diagnosis, while strategic support and cooperative care between primary care physicians and geneticists can improve long term management.

Introduction

The expansion of genetics and genomics in medicine has resulted in an increased role for primary care physicians (PCP) to integrate genetics and genomics into their practice, including assessing and educating patients about genetic risks and management of some genetic disorders. PCPs serve as a point of first contact for patients within the health care system, emphasizing their role in identifying patients with genetic conditions, and potentially providing further evaluation and management as guidelines become more available for patients with a genetic disorder. Even though medical geneticists have the primary role in diagnosing and managing genetic conditions, access to specialists may be limited, and the importance of early diagnosis and management has advanced over the last decade with the evolution of genetics and genomics medicine. Providing the appropriate education and resource tools to the PCPs will help to improve their daily practice with engagement of genetics care and broad access to evidence-based genetic testing for their patients. In some cases, surveillance and management may be shared between the PCP and the geneticist, while in others, the PCP may take over surveillance entirely, with support from the geneticist available as needed. Finally, the longitudinal relationship built between the PCP and the family is essential in understanding the familial dynamics and psychosocial issues which can be raised by diagnosis of a genetic disorder.

The Pediatrician’s Role in Newborn Screening Follow-up

One of the primary care pediatricians’ essential roles is management of newborn screening. Newborn screening is essential for the diagnosis of potentially fatal or disabling conditions so that treatment can be initiated as early as possible. The newborn metabolic screen is designed to have a high sensitivity and low false negative rate, so that all true cases of the disease are identified and none are missed. While some of these screening tests are highly specific with a low false positive rate, others may have a higher false positive rate or higher number of infants that need rescreening. Because of this goal to identify all affected infants accurately, specific diagnostic tests are still necessary to confirm or refute a diagnosis.

All infants born in a medical setting should have a newborn screen performed prior to discharge. If newborn screening was not obtained due to circumstances such as home birth, emergency birth, hospital transfers, international adoptions, or parents’ refusal, the pediatrician should arrange the specimen collection during the first newborn visit. In the case of parental refusal, the pediatrician should educate the parents regarding the benefits of newborn screening. Educational resources appropriate for the lay person can be provided, such as Baby’s First Test https://www.babysfirsttest.org), or the American Academy of Pediatrics’ website for families (https://www.healthychildren.org). The lack of screening should then be added to the patient’s chart to prompt an evaluation if there is a concern in the child’s growth or development, vomiting, seizures, developmental delay, lethargy, or poor feeding.

The pediatrician should also monitor for results of the initial newborn screen. Some of the conditions on the newborn screen can be fatal if immediate action is not taken. The timeframe for follow-up and referral varies depending on the abnormal screening results. For some disorders, for example maple syrup disease, congenital adrenal hyperplasia, and methylmalonic aciduria, immediate treatment and follow-up would be necessary. In other cases, the newborn screen may only need to be repeated, such as if the initial screen was not sufficient or had a borderline or low risk result. PCPs may also be able to order confirmatory testing as necessary for an abnormal newborn screen, collaborating with genetics teams at the newborn screening referral sites.¹

If more information is desired, the American College of Medical Genetics (ACMG) has developed web-based resources called action (ACT) sheets to guide physicians through preliminary responses to newborn screening results. ACT sheets are located at ACMG’s website (www.acmg.net) and provide focused algorithms to summarize the possible diagnoses, description of the conditions, actions that need to be taken for diagnostic evaluation, and reporting requirements. ACT sheets also give state-specific information for the referral resources. More information about the newborn screening program specific to Missouri can be found on the Missouri Department of Health’s website (https://health.mo.gov).

Most importantly, PCPs are typically the initial point of contact with families about positive newborn screen results. The longitudinal and trusting relationship between the family and primary pediatrician is an asset when discussing newborn screening results, which can cause anxiety in new parents. The pediatrician can educate the family about the need for additional testing to confirm or refute a diagnosis. Providing some basic resources to families about the disorder, such as referring them to the newborn screening informational resources as above, can relieve parental anxiety while confirmatory testing is ongoing.

If a genetic diagnosis is confirmed after a positive newborn screen, the infant will have ongoing management with a geneticist. Since most of the possible conditions in newborn screening are hereditary, genetic counseling will also be beneficial for the family: carrier testing studies can be offered for the parents to determine recurrence risk in siblings, and testing may be available for the siblings and potentially other relatives as well.

Primary Care Physician’s Role in Identifying Patients at Risk for a Genetic Disorder

One of the pediatrician’s primary roles is to ensure that each child’s health and development is proceeding as expected. Because of this, pediatricians are experts in identifying what is normal versus what is atypical or out of the ordinary. Pediatricians should be aware of potential clues or red flags that could indicate an underlying genetic disorder (Table 1).

Table 1.

Symptoms which could indicate a genetic diagnosis.

Similarly, primary care physicians for adults are trained in the typical progression of diseases seen in adults. With respect to genetic disorders, the single most important role for the PCP is to consider the possibility of an underlying genetic diagnosis. A patient with a genetic disorder may present with an unusual symptom, multiple unusual symptoms in the same person, lack of response to treatment, or a more severe progression than typical for a specific problem. For example, the presence of an LDL-C >190 mg/dL and a first degree relative with premature coronary artery disease indicates a diagnosis of familial hypercholesterolemia.² Or, a young adult who presents with an unusual combination of distal weakness, fatigue, cataracts, cardiac arrhythmia, and dysphagia may have myotonic dystrophy type 1. However, in some cases, the signs of a genetic disorder may be more subtle. An individual with fatigue, joint pain, and liver function abnormalities may have typical aging and possibly a fatty liver; or, they could have a genetic condition like hemochromatosis, which requires targeted treatment of iron overload. Screening tests with iron studies could differentiate the scenarios, but the physician must be aware of the possibility in order to consider screening.

Given the significant workload placed on primary care physicians, ways to improve screening for genetic conditions without placing additional time burdens on the PCP are under investigation, such as system level screening for common conditions. In one study, a case-finding tool for familial hypercholesterolemia (FH) was applied to the electronic medical record to identify adults at increased risk. Individuals identified by the tool completed a questionnaire and if still screen positive were offered genetic testing for FH.³ This tool identified many affected individuals which allowed specific treatment for their disorder. Another study, a randomized controlled trial called BRIDGE (Broadening the Reach, Impact, and Delivery of Genetics Services) is comparing uptake of genetic counseling, update of genetic testing, and patient adherence to management recommendations when identified by an automated algorithm analyzing family history data in the electronic medical record versus standard of care delivery models.⁴

Family history is also a necessary component of the primary care evaluation. Detailed family history can be essential to identify the risks of genetic conditions that might be prevented and need close monitoring or referral.^5,6 Obtaining a multigenerational pedigree or family tree would be the most informative in assessing risk of a genetic disorder, although such an extensive history may not be practical in the typical primary care practice. The minimum family history should include documentation of what diagnoses are present in the family, the ages of the condition onset, and the relationship of the family members (parent, cousin, grandparent, etc.). If a pattern is noticeable such as multiple affected family members with the same condition, early age of onset of cancer, ethnic background associated with certain conditions (i.e., breast cancer risk in those of Ashkenazi ancestry), or multiple affected family members with neurodevelopmental delay or intellectual disability, then the family should be referred for genetic evaluation.

One important reason for adequate family history is cancer risk assessment. For example, the United States Preventative Services Task Force (USPSTF) recommends that women with a family history associated with increased risk for BRCA1 or BRCA2 be referred for genetic counseling and possible testing.⁷ In 2013, the USPSTF clarified that PCPs should conduct the proactive risk assessment for breast and ovarian cancers. However, one study by Linfield in 2022 showed that only 22% of high-risk patients in their large integrated health system in Cleveland were appropriately referred for genetic counseling.⁸ These results are similar to a National Health Interview Survey, which found that 24% of patients met criteria for genetic testing but only 9% were referred.⁹ Given the burdens placed on PCPs, screening tools have been created to assist PCPs with risk assessment and some EHRs may include an integrated Hereditary Breast and Ovarian Cancer (HBOC) risk calculator, although these tools may not capture all relevant cases or all information necessary to monitor utilization when considering health disparities.^10,11 Adding another layer of complexity is that guidelines for screening for cancer syndromes change over time, making it necessary for the PCP to maintain awareness of the current recommendations. Additional research is still needed to optimize integration of cancer risk assessment and simplify the screening process to improve uptake.

Primary Care Physician’s Role in Evaluation and Diagnosis

Ideally, once a patient is identified with a symptom concerning for a genetic disorder, the patient would be referred to a genetic specialist. However, the increasing awareness of genetic conditions in the general population and the rapid expansion of available genetic testing has led to increased demand for genetic evaluation. In some areas, access to a geneticist may be difficult due to distance and lack of ability to travel, or the wait time for an appointment with a geneticist may be long. Incorporating genetic testing into primary care practice could shorten the time to diagnosis and benefit the patient, while also decreasing healthcare costs by avoiding specialist visits and travel.

However, the process of choosing the most appropriate genetic test and navigating insurance is complex, as outlined by Lee et al. in the July/Aug 2022 issue of Missouri Medicine.¹² For example, as recently as 2010, the American Society for Human Genetics recommended chromosomal microarray as the first line genetic test for individuals with global developmental delay, intellectual disability, and multiple congenital anomalies with a diagnostic yield of 15–21%.^13–15 However, with the evolution in genetic testing techniques and methods, the number of identifiable genetic conditions has significantly expanded. As of 2021, the American College of Medical Genetics published guidelines recommending WES/WGS as the first or second line test for the same indications, based on new data that broad based testing with exome or genome sequencing has an increased diagnostic yield of 38%.^16–17 While it is uncommon for a PCP to utilize WES/WGS in their clinics due to its complexity, the evolving recommendations for appropriate testing illustrate the challenge a PCP may face in staying up to date in genetics.

Studies exploring barriers for PCPs ordering genetic testing have shown perceived barriers of lack of education and confidence, and lack of access to formal and informal consultation with specialists.¹⁸ Many physicians in practice completed their medical training prior to clinical availability of tests like CMA and exome sequencing, creating a knowledge gap. If a PCP would like to incorporate genetic testing into their practice, educational resources have been developed by several organizations to increase their knowledge about ordering genetic testing and results interpretation (Table 2).

Table 2.

Educational resources available for physicians.

The American Medical Association - Educational Hub for Genetics and Genomics

Short learning modules - 0.5 CME/each https://edhub.ama-assn.org/collections/5664/genetics-and-genomics

The American College of Medical Genetics and Genomics

Genetics101 for Healthcare Providers - 5 CME https://www.acmgeducation.net/Public/Catalog/Main.aspx

The Heartland Regional Genetics Network (HGRN)

Provides education about the process of genetic testing, including pre-test counseling, evaluation, post-test counseling, follow up https://www.heartlandcollaborative.org/resource-center/

Other resources

Genetic Testing Registry - database of available tests: https://www.ncbi.nlm.nih.gov/gtr/ The US Preventive Services Task Force - screening recommendations: https://www.uspreventiveservicestaskforce.org/uspstf/ The Centers for Disease Control and Prevention’s Office of Public Health Genomics - precision health https://www.cdc.gov/genomics/default.htm

A progressive model for care has also been proposed (Figure 1), where PCPs could monitor their patients for symptoms that could suggest a genetic disorder. If they felt comfortable in doing so, they could order testing for the condition independently (Table 3). If needed, support could be provided to the PCP by the specialist for simple questions. More complex patients would be referred directly to the geneticist for consultation.¹⁸ Research is still ongoing to determine the utility and the most effective way to structure such arrangements. For example, at Washington University in St. Louis and St. Louis Children’s Hospital, we provide support to PCPs through phone consultation with genetics specialists and accept referrals for both adult and pediatric patients.

Figure 1.

Proposed progressive model of care with escalating support from medical geneticists.

Adapted from Harding et al. BMC Medical Education (2019) 19:195.

Table 3.

Common indications for genetic testing and tine recommended first line test for tine indication.

Indications	Recommended First Line Genetic Test
Global developmental delay or Intellectual disability	Exome or genome sequencing
Multiple congenital anomalies	Exome or genome sequencing
Autism spectrum disorder	Chromosomal microarray and Fragile X for males
One specific gene or suspected disorder, or family history of a known gene variant	Targeted testing
Single symptom (ie, epilepsy)	Gene panel for that symptom
Down syndrome. Turner syndrome, or concern for a translocation or structural anomaly	Karyotype

Investigation is also ongoing regarding other potential tools to expand genetics services. A pilot “eConsultation” service was trialed in Canada, where PCPs utilized an asynchronous web-based application to submit clinical questions to a geneticist. The geneticist was then able to provide recommendations, including requesting additional information or referral for genetic evaluation. This service allowed the PCP to obtain necessary information and avoid referral in 47% of cases where a referral had initially been considered. Post consult surveys showed that the PCPs reported this service to be of high value for both the PCP and the patient.¹⁹

In addition to choosing the correct test, a primary care physician who orders genetic testing also has a legal and ethical duty to provide adequate informed consent, especially for broad tests such as exome and genome sequencing. Informed consent should include a discussion of: the risks, benefits, and limitations of testing; the possibility of uncovering information which is incidental to the reason for testing or that alters familial relationships such as non-paternity; implications of test results for other family members; cost; and other possible consequences such as anxiety or the possibility of genetic discrimination.^20–21,23 The Genetic Information Nondiscrimination Act (GINA) prevents discrimination in health insurance and most employment, but patients should be made aware that there are exceptions to this protection. If a patient has a positive test for a genetic disease, they may become ineligible for life, long-term care, or disability insurance. Another important exception to GINA is that it does not apply to the members of the United States military or those who receive medical insurance through the federal government, such as through the Veterans Administration.²²

For the PCP who may want to order genetic testing, choosing the correct test and completing the ordering process is only the first step. The interpretation of genetic test results is also complex: the physician must understand whether a variant identified on a test is pathogenic or causative of disease, versus a benign variant, or potentially a variant of uncertain significance. Variants of uncertain significance are frequently identified on sequencing panels, but do not automatically provide a diagnosis and in most circumstances are not medically actionable without additional information and analysis. As discussed by Green and Toll in the July/August 2022 issue of Missouri Medicine, physicians have the legal and ethical responsibility to accurately communicate to the patient all results of genetic testing and the implications of the results for the patient’s future health, since this information could affect the patient’s ability to make informed decisions about their medical care.^12,23 Ultimately, it is the responsibility of the physician to ensure they have adequate training in determining the appropriate test to order and to interpret and counsel the patient or family about the results.

Primary Care Physician’s Role in Management of Genetic Disorders

Primary care pediatricians play a significant role in managing confirmed genetic conditions by monitoring symptoms and applying health maintenance recommendations specific to the condition. Any child with a significant medical condition or diagnosis including a genetic disorder should have a medical home with a primary pediatrician.²⁴ A child with special health care needs or a chronic disorder will likely need diagnosis-related subspecialty visits, written care plans, appropriate patient and family educations, and regular comprehensive follow up visits. Longitudinal follow-up appointments, referrals, and surveillance could all be managed by pediatricians if they are comfortable in doing so.

The American Academy of Pediatrics and the American College of Medical Genetics have published medical management guidelines for several common genetic conditions to empower PCPs to manage longitudinal care for these patients. For example, medical management guidelines exist for achondroplasia, Down Syndrome, Turner Syndrome, Fragile X, Noonan Syndrome, and others.^25–30 These management guidelines provide information about the clinical presentation of the disorder, natural history, possible complications, and specific outlines for the recommended monitoring and surveillance tests to perform over time. Management of this surveillance by the PCP may allow for more frequent monitoring and earlier recognition of complications. The close longitudinal care can also build the relationship with the PCP and improve these patients’ quality of life.

Similarly, primary care physicians for adults can also manage a cohort of their patients with common genetic disorders. For example, individuals who are homozygous for a common variant causing hemochromatosis, HFE C282Y, may never show evidence of iron overload, but should have routine monitoring of iron studies.³¹ Individuals with familial hypercholesterolemia could initially be managed by the PCP, including pharmacotherapy with statins, reducing CAD risk factors such as cessation of smoking and healthy diet, and treatment of hypertension.³² If cholesterol levels are not sufficiently reduced with standard therapies, referral to a lipid specialist with expertise in FH would be indicated.

Conclusion

The rapid expansion of interest in genetics and the availability of genetic testing has led to increased need for genetics services. Given their longitudinal relationships with patients and their ability to recognize unusual symptoms, the primary care physician is optimally placed to recognize when a genetic disorder could be present and to initiate an evaluation. While barriers to extensive genetic testing in the primary care setting certainly exist, such as time and insurance difficulties, educational resources and cooperative models of care with geneticists may expand opportunities and facilitate earlier diagnosis and treatment.