Genetic screening is a population- based method to identify persons with increased susceptibility to a particular genetic disease. Screening at the population level is not to be confused with testing for affected persons or for carriers already identified because of family history. Although family history is a very useful tool (Fig. 1), no one except an identical twin shares all variants with another family member. Family history is only an indirect means of assessing the contribution that an individual’s own combination of genetic variants might make to disease. Family history is also an insensitive indicator of susceptibility, as it depends on disease being overt in the relatives of the individual concerned.

Fig1. Cumulative incidence (per 10,000) of colon cancer versus age in individuals with and without a family history of the disease. Data from Fuchs CS, Giovannucci EL, Colditz GA, et al: A prospective study of family history and the risk of colorectal cancer, N Engl J Med 331:1669– 1674, 1994.

The challenge going forward is to screen populations, independent of family history and independent of clinical status, for variants relevant to health and disease and to apply this information to make risk assessments that can be used to improve the health care of an individual and the family.

The objective of population screening is to examine all members of a designated population, regardless of family history. Applying the information derived requires demonstration that genetic risk factors are valid indicators of actual risk in an individual and, if valid, that such information is useful in guiding health care. Genetic screening for disease susceptibility is an important public health activity that will become more significant as more and better screening tests become available.

Newborn Screening

The best- known population screening efforts in genetics are government- supported or - mandated programs that identify presymptomatic infants with diseases for which early treatment can prevent, or at least ameliorate the consequences. For newborn screening, the anticipated disease is generally not assessed by directly determining the genotype. Instead, in most instances, asymptomatic newborns are screened for abnormal levels of various substances in the blood. Abnormalities thus identified trigger further evaluation to confirm or rule out the presence of a disorder. One exception to this paradigm of using a biochemical measurement to detect a disease- causing genotype is screening for abnormalities in hearing, in which the phenotype itself is the target of screening and intervention. While typically using blood taken from a heelstick, more recent newborn screening expansion has included bedside testing to detect conditions such as hearing loss and cardiac disease. The latter 2 conditions are now included in the U.S. federally recommended uniform screening panel (RUSP)2 and are included in some programs in other parts of the world.

Many of the general issues concerning genetic screening are highlighted by newborn screening programs. A determination of the appropriateness of newborn screening for any particular condition is based on a standard set of criteria involving clinical validity and clinical utility (see Box 1). The design of newborn screening tests includes keeping false- negative rates low so that true- positive cases are not missed, without making the test so nonspecific as to drive the false- positive rate unacceptably high. False- positive results cause unnecessary anxiety to the parents and increase costs, because more unaffected infants have to be recalled for retesting. At the other extreme, false- negative results vitiate the purpose of a screening program. In deciding whether to institute screening for any given condition, consideration must be given to the ability of the public health system infrastructure to handle the care of affected newborns so identified through such screening.

Box1. GENERAL CRITERIA FOR AN EFFECTIVE NEWBORN SCREENING PROGRAM

The prototype condition that satisfies all of these criteria is phenylketonuria. For decades, finding elevated levels of phenylalanine in a spot of blood on filter paper obtained soon after birth has been the mainstay of neonatal screening for phenylketonuria and other forms of hyperphenylalaninemia. Currently, this applies throughout North America and Europe, most of Latin America and much of Asia Pacific. A positive screen result, followed by definitive confirmation of the diagnosis, leads to the institution of dietary phenylalanine restriction early in infancy, thereby preventing irreversible intellectual disability.

Two other conditions that are widely targeted for newborn screening are congenital hearing loss and con genital hypothyroidism. Newborn screening for hearing loss is mandated throughout the United States and Canada. Approximately half of all congenital deafness is due to single- gene defects. Infants found to have hearing impairments by newborn screening are offered intervention with sign language, cochlear implants, and other communication aids early in life, meant to improve their long- term language skills and intellectual abilities beyond those seen if the impairment is discovered later in childhood. Screening for congenital hypothyroidism, a disorder whose genetic basis is known in only 10 to 15% of cases, but is easily treatable, is universal in the United States and Canada and routine in many other countries. Thyroid hormone replacement therapy started early in infancy completely prevents the severe and irreversible intellectual disability caused by congenital hypothyroidism. Thus, both hypothyroidism and congenital hearing loss easily fulfill the criteria for newborn screening.

A number of other disorders, such as galactosemia, sickle cell disease, biotinidase deficiency, severe combined immunodeficiency, and congenital adrenal hyperplasia, are part of many or most neonatal screening programs. Which disorders should be the target of newborn screening varies among jurisdictions. In the United States, Recommended Universal Screening Panel (RUSP) is a national guideline listing conditions for which the U.S. Secretary of Health and Human Services recommends all newborns be tested.

Standards for newborn screening differ widely around the globe. Which disorders should be the target of newborn screening varies from province to province in Canada without a national consensus. As of 2022, the United Kingdom’s national program to screen newborns across all jurisdictions included just nine disorders.

Tandem Mass Spectroscopy

 For many years, most newborn screening was performed by a test specific for each individual condition. For example, phenylketonuria screening was based on a microbial or a chemical assay that tested for elevated phenylalanine level. This situation has changed dramatically with the application of the technology of tandem mass spectrometry (TMS). Not only can a neonatal blood spot be examined accurately and rapidly for an elevation of phenylalanine, with fewer false positives than with the older testing methods, but TMS analysis can simultaneously detect a few dozen other biochemical disorders. Some of these, such as homocystinuria or maple syrup urine dis ease, were already being screened for by individual tests (Table 1). TMS, however, does not replace the disease- specific testing methods for other disorders currently included in some newborn screening, such as galactosemia, biotinidase deficiency, congenital adrenal hyperplasia, and sickle cell disease.

Table1. Disorders Detectable by Tandem Mass Spectrometry

TMS also provides a reliable method for newborn screening for some disorders that fit the criteria for screening but had no reliable newborn screening program in place. For example, medium- chain acyl- CoA dehydrogenase (MCAD) deficiency is a disorder of fatty acid oxidation that is usually asymptomatic but manifests clinically when the patient becomes catabolic. Detection of MCAD deficiency at birth can be lifesaving. Affected infants and children are at very high risk for life- threatening hypoglycemia in early childhood during the catabolic stress caused by an intercurrent illness, such as a viral infection; nearly 25% of children with undiagnosed MCAD deficiency will die with their first episode of hypoglycemia. The metabolic derangement can be successfully managed if it is treated promptly. In MCAD deficiency, alerting parents and physicians to the risk for metabolic decompensation is the primary goal of screening. The children are healthy between attacks and do not require daily management other than avoidance of prolonged fasting.

TMS provides a rapid test for many disorders for which newborn screening is already being done or can easily be justified. TMS also identifies infants with inborn errors—such as ethylmalonic acidemia—that have not generally been the targets of newborn screening because of their rarity and difficulty of providing definitive therapy to prevent the progressive neurologic impairment. TMS can also identify abnormal metabolites whose significance for health are uncertain. For example, short- chain acyl- CoA dehydrogenase (SCAD) deficiency, another disorder of fatty acid oxidation, is most often asymptomatic, although a few individuals may have difficulties with episodic hypoglycemia. Thus, a positive TMS screen result is not particularly predictive of developing symptomatic SCAD later in life. Although TMS can identify many metabolic disorders, does the benefit of detecting disorders such as SCAD deficiency outweigh the negative impact of raising parental concern for most newborns whose test result is positive but who will never be symptomatic? Thus not every disorder detected by TMS fits the criteria for newborn screening. Some public health experts argue that only those metabolites of proven clinical relevance should be reported to parents and physicians.

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مواضيع ذات صلة

Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome

Genetic Counseling for Preconception and Prenatal Diagnosis and Screening

Fetal Surgical and Medical Interventions

X-Linked Inheritance

Preconception Genetic Screening and Testing

Problems in Prenatal Chromosome Analysis and Gene Sequencing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects