Preventative genetic screening – single gene, genetic panel, or whole-genome?

 Highlights:

• Genetic screening can be used to detect variations in a single gene, range of genes (panel testing), or genome
• Genetic screening is routinely used in clinical practice to diagnose and prevent hereditary conditions and rare diseases
• Preventive genomic screening is now being considered a powerful tool to maintain population health
• Genetic screening can be beneficial for healthy aging
• Though the genetic screening can show gene variations linked to longevity, it cannot yet be used to predict lifespan due to the influence of environmental and lifestyle factors

Introduction

According to the Online Mendelian Inheritance in Man database, more than six thousand diseases have a proven genetic basis, and more associations are discovered rapidly. With the growing accessibility of the testing techniques and available amounts of genome-wide association data, genetic screening has become one of the most prominent tools in the medical field. Doctors routinely employ it for diagnostics and to evaluate the risk of developing diseases. And multiple at-home kits are available for individual use. Moreover, sequencing of the entire genome is completed nowadays in days to weeks and is included as an analysis technique in multiple hospitals worldwide.

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When did the genetic screening start?

Genetic testing timeline can be generally divided into two periods (1) – before the human genome project and after. The first genetic test appeared as early as the 1950s, discovering that an additional copy of the 21^st chromosome causes Down’s syndrome. In the 1960s, phenylketonuria screening became quite common. Through the ‘80s and ‘90s, DNA testing became the routine part of a police investigation, and by the beginning of the 2000s, a range of genetic tests made their entrance into the clinical practice, initially being rather expensive and applicable only to monogenic (caused by a single gene) diseases. After 2000, the human genome was deciphered, technology started becoming more economically available, and microarrays (technology of placing thousands of gene sequences on a solid surface) along with genotyping (technology that allows to link small genetic differences to phenotype changes) launched not only a new wave of research but a new industry - direct-to-consumer (or at-home) DNA testing.

Types and applications of genetic screening

Genetic tests can be used for a variety of purposes (2), such as:

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• Diagnosing a rare health condition,
• Preimplantation and prenatal screening,
• Detecting whether an inherited health condition can affect a patient’s children,
• Estimating risks of getting certain health conditions,
• Guiding doctors on the applicability of prescribed treatment or whether a patient can join a particular clinical trial.

Depending on the condition, genetic testing can be used to detect changes in (2):

• Single gene,
• Panel testing, which includes monitoring changes in multiple genes at a time,
• Large-scale genomic testing

Single gene testing is applied to detect a specific disease or syndrome that can be linked to a variation of one gene, such as Duchene muscular dystrophy or sickle cell disease. It can also be used to trace a known genetic mutation within a family. Panel testing is targeted at the conditions linked to a group of genes like epilepsy. Frequent application of panel testing is also an estimation of developing certain types of cancer (e.g., breast or colorectal cancer). In complicated cases, when a comprehensive analysis is needed, a patient can undergo large-scale genetic or genomic screening. Two main types of large-scale genetic screening exist: exome sequencing and genome sequencing. The exome refers to the an important protein-coding part of DNA, constituting around 1-2% of the genome and playing role in multiple pathways and processes. The genome includes both coding and non-coding regions of DNA. Genetic tests provide qualitative results that can be positive, negative, or inconclusive.

Diagnostic screening

The diagnostic power of genetic screening lies in its ability to identify dangerous and/or rare conditions. The most common cause of assigning genetic screening is when a patient has an unusual combination of symptoms, complex family disease history, or is already diagnosed with a common disease such as cardiomyopathy, epilepsy, or congenital heart disease. Examples of rare diseases that can be diagnosed include, among others, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, and Lynch syndrome. DNA sample can be collected from blood or saliva (via cheek swab) in most cases, or using amniotic fluid (for prenatal screening) or hair. 

Genetic screening is a vital healthcare component for newborns and is implemented now in all developed countries (3). In the United States, in most states, newborns are screened for at least 29 conditions (4), including amino acid disorders (such as phenylketonuria), fatty acid oxidation disorders, endocrine disorders, and others.

For diagnostic purposes, both single-gene and panel testing can be used, but genome sequencing is broader in scope. The data obtained from it can be used both to analyze diagnostic hypotheses and to generate new ones.

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Preventive screening

Preventive genetic screening is used to estimate the risks of developing a certain condition and is based on the analysis of family disease history. Preventive screening is also employed for workers in dangerous conditions, such as work with hazardous chemicals, radiation, etc. Cancer screening is one of the most widely used reasons to undergo genetic screening nowadays. The most known examples are breast and ovarian cancers. The heightened risk of developing these cancers is strongly linked to the variations in BRCA1/2 (breast cancer 1/2) genes (5). The range of other cancers with strong hereditary links is also routinely tested in clinical practice, including colorectal, uterine/endometrial,  pancreatic cancers, and melanoma (6).

Another field for preventative genetic screening is pre-implantation screening used prior to fertilization (7). Employing preimplantation genetic screening was shown to improve both embryo health and pregnancy rates.

From the preventive perspective, more resonance gains the idea of using large-scale genomic screening in general populations. Existing genomic screening programs aim to screen as many individuals as possible to target preventable or curable conditions. An example of such a program is the Geisinger MyCode Community Health Initiative, which used preventive genomic screening of all participants’ DNA data (8). This screening targeted 76 genes linked to 27 medically actionable conditions.

Genetic screening and aging

Effective genetic screening in its preventive aspect is strongly linked to healthy aging. Knowing the patient’s family history and connected risks, the medical professional can advise genetic screening to eliminate or confirm the possibility of developing age-related diseases, particularly cancer. Another disease with a strong genetic component is Alzheimer’s disease. People with an APOE (apolipoprotein E) e4 gene variation have a 90% risk of developing the disease (9).

As for estimating longevity, single-gene and panel testing have minimal power and generally are not applied for that purpose. The reason behind it is that many genes are known to be linked with longevity – examples being FOXO3 (forkhead box O3), CETP (cholesteryl ester transfer protein), and APOE (10) – the longevity effect of “beneficial” gene variation is not guaranteed. The mechanisms behind longevity are complex and intertwined, and not only genetics plays a role, but also epigenetics – how lifestyle and environment influence gene expression. Though a person might be a carrier of “favorable” or “unfavorable” gene, this gene’s expression might get altered due to the functional changes in the genome.

Nevertheless, even with the lack of genetic tests for longevity, large-scale genomic screening is a valuable tool to identify common gene variations in people with exceptional longevity and make a link between human and animal studies.

Who is a genetic counselor?

Suppose your patient or client has indications for panel testing or large-scale genomic screening. In that case, they can be directed to a genetic counselor – a health professional with specialized training and experience in genetics. The role of a genetic counselor (11) is to help people understand and adapt to the implications of a genetic contribution to the disease. The process of counseling includes interpretation of family and individual’s medical history, education about genetic testing, and help with making an informed choice. In cases when a patient considers large-scale genome or exome screening, a genetic counselor is required to estimate a balance of benefits and costs.

At-home genetic screening kits

As was mentioned before, a range of companies suggests at-home (or direct-to-customer) genetic screening kits (12). These kits are targeted at various endpoints – from detecting one’s ancestry to diagnostic tests. At-home genetic kits are quite accessible (compared to laboratory testing) and have been primarily used as a tool for identity-seeking. However, if your client or patient intends to use an at-home kit for a medical purpose, it is worth noting that most of the existing commercial kits have not been extensively validated and are not approved by FDA. At the moment, only several tests from 23andMe company were approved by FDA, including kits for Bloom syndrome (a rare inherited disorder linked to a greatly increased risk of cancer), BRCA1/2, general health risks, and pharmacogenetics (13). However, it should be remembered that even approved tests usually cover a limited number of genetic variants (and can limited in use to people of european descent), the waiting time for the results can be long, and their usage should be adjusted for individual needs.

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Risks and concerns

Large-scale genomic screening is being more and more included in clinical practice, and those interested can use at-home kits. However, a few concerns (14) remain, the major being the interpretation and disclosure of data. Any type of genetic sequencing should not be treated as a diagnostic panacea, and there is still a place for false-positive results, misinterpretations, and ambiguous diagnoses. Secondly, even when employing genomic screening, it’s important to remember that certain ethnic groups are underrepresented in genomic databases, which may lead to incorrect diagnostics. And thirdly, patients and health professionals should carefully monitor how the screening data is used and distributed, especially in the case of at-home kits.

Conclusions

Genetic screening is a non-invasive and efficient technique that allows the prevention and diagnosis of multiple life-threatening conditions. Genome and exome sequencing are anticipated to become the main diagnostic tool to detect and prevent genetic conditions with high heterogeneity (having many candidate genes). Though some concerns, as with any tool, remain, the genetic (and particularly, large-scale genomic) screening has proven and continues to prove its efficiency for multiple patients. However, genetic risks are not finite sentence due to multiplicity of factors influencing gene expression, but rather a guideline for disease prevention and healthier lifestyle. 

References

1.         Durmaz AA, Karaca E, Demkow U, Toruner G, Schoumans J, Cogulu O. Evolution of Genetic Techniques: Past, Present, and Beyond. BioMed Res Int. 2015;2015:1–7.

2.         Burke W. Genetic Testing. Guttmacher AE, Collins FS, editors. N Engl J Med. 2002 Dec 5;347(23):1867–75.

3.         Alexander D, van Dyck PC. A Vision of the Future of Newborn Screening. Pediatrics. 2006 May 1;117(Supplement_3):S350–4.

4.         Watson MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR, American College of Medical Genetics Newborn Screening Expert Group. Newborn Screening: Toward a Uniform Screening Panel and System—Executive Summary. Pediatrics. 2006 May 1;117(Supplement_3):S296–307.

5.         Pujol P, Barberis M, Beer P, Friedman E, Piulats JM, Capoluongo ED, et al. Clinical practice guidelines for BRCA1 and BRCA2 genetic testing. Eur J Cancer. 2021 Mar;146:30–47.

6.         LaDuca H, Polley EC, Yussuf A, Hoang L, Gutierrez S, Hart SN, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med. 2020 Feb;22(2):407–15.

7.         Sullivan-Pyke C, Dokras A. Preimplantation Genetic Screening and Preimplantation Genetic Diagnosis. Obstet Gynecol Clin North Am. 2018 Mar;45(1):113–25.

8.         Carey DJ, Fetterolf SN, Davis FD, Faucett WA, Kirchner HL, Mirshahi U, et al. The Geisinger MyCode community health initiative: an electronic health record–linked biobank for precision medicine research. Genet Med. 2016 Sep;18(9):906–13.

9.         Ward A, Crean S, Mercaldi CJ, Collins JM, Boyd D, Cook MN, et al. Prevalence of Apolipoprotein E4 Genotype and Homozygotes (APOE e4/4) among Patients Diagnosed with Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2012;38(1):1–17.

10.       Murabito JM, Yuan R, Lunetta KL. The Search for Longevity and Healthy Aging Genes: Insights From Epidemiological Studies and Samples of Long-Lived Individuals. J Gerontol A Biol Sci Med Sci. 2012 May 1;67A(5):470–9.

11.       Resta R, Biesecker BB, Bennett RL, Blum S, Estabrooks Hahn S, Strecker MN, et al. A New Definition of Genetic Counseling: National Society of Genetic Counselors’ Task Force Report. J Genet Couns. 2006 Apr;15(2):77–83.

12.       Su P. Direct-to-consumer genetic testing: a comprehensive view. Yale J Biol Med. 2013 Sep;86(3):359–65.

13.       FDA: Direct-to-consumer tests [Internet]. [cited 2022 Oct 4]. Available from: https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct-consumer-tests#list

14.       Costain G, Cohn RD, Scherer SW, Marshall CR. Genome sequencing as a diagnostic test. Can Med Assoc J. 2021 Oct 25;193(42):E1626–9.

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