Exciting developments in the fields of genetics and genomics have facilitated the identification of the etiological basis of many Mendelian disorders. Several of the methods used in gene discovery have focused initially on homogeneous populations, including the Ashkenazi Jewish population. The founder effect is well recognized in this community, in which historical events and cultural behaviors have resulted in a limited number of mutations underlying genetic disorders with substantial health impact. New technologies have made it possible to rapidly expand the test panels, changing testing paradigms, and thereby creating challenges for the physician in deciphering the appropriate approach to genetic screening in this population. The goal of this review is to help primary obstetric health care providers navigate through this quickly moving field so as to better counsel and support their patients of Ashkenazi Jewish heritage.
Recently published data from the 1000 Genomes Project suggest that everyone carries approximately 50-100 variants previously implicated in inherited disorders. For recessive conditions, individuals who have 1 normal allele and a disease causing mutation in the other allele are considered carriers but will not develop the condition, whereas children of carrier couples will have a 1 in 4 risk of being affected with the disease.
Carrier screening ideally seeks to identify, preferably at the preconception stage, individuals who are carriers of such genetic conditions. This allows carrier couples to anticipate pregnancies that may be at increased risk for genetic disorders and choose among several reproductive strategies or alternatively prepare for the birth of an affected child.
Although it is still not possible to screen for all known conditions in all populations with a universal testing system, targeted screening approaches have become integrated into clinical care. One of the most successful targeted programs has led to the almost complete eradication of Tay-Sachs disease (TSD) from the Ashkenazi Jewish (AJ) population. The results of the TSD program, initiated in the 1970s, illustrate the public health perspective that informs most successful population wide screening programs.
The first and most important criterion for the selection of TSD as an appropriate condition for prenatal or preconception screening was the high incidence of the disorder, approximately 1:3600 TSD cases in AJ newborns. Also specific for this condition was the early availability of a robust and cheap biochemical enzyme assay that could identify almost all carriers and also be used for prenatal diagnosis.
The success of the TSD carrier screening program included the fact that it was community driven to a large extent. For example, the Dor Yeshorim program addressed the needs and concerns of a very traditional Orthodox Jewish community with regard to prohibitions against termination of pregnancy as well as potential stigma and labeling of carriers. Jews of other less restrictive denominations likewise partnered with the medical community further contributing to a culturally sensitive and successful model. Since the initiation of the TSD programs, other carrier screening programs have been adopted and endorsed by the American College of Obstetricians and Gynecologists (ACOG), including screening for hemoglobinopathies in high-risk populations as well as pan-ethnic testing for cystic fibrosis (CF).
Characteristics of the AJ population that underlie the feasibility of expanded genetic carrier screening programs
In populations of defined ancestries, specific variants are found in a higher proportion than in individuals of diverse ancestries. There are several reasons for this phenomenon, usually related to well-known mechanisms of population genetics. The European AJ population, originating from the Middle East, underwent migrations and contractions leading to a bottleneck effect in which only a relatively small number of variants were transmitted to the descendants during subsequent population expansions. A mutation that was present in one of these few individuals (a founder) in the original population was thereby transmitted to a resulting relatively genetically homogeneous population of descendants in which there was minimal interpopulation cross-mating. The result is a significant proportion of recessive diseases caused by a relatively small number of mutations.
This mechanism is not unique to the AJ population and explains why TSD is also frequent in the French Québécois population, who are the descendants of a small group of migrants from France. Of note, the founder mutations for this population are different from the classic AJ Tay-Sachs mutations.
In the last decades, in part because of the Human Genome Project, the causal genes identified and the number of diseases for which carrier screening is available has progressed far beyond TSD, and this trend is expected to continue. Paradoxically, as is often the case with technological breakthroughs, such developments can be a source of uncertainty as well as a welcomed benefit to both providers and patients.
The difficult choice: what disorders should the obstetrician-gynecologist provider offer to AJ individuals for optimal carrier screening?
Professional recommendations
Professional societies, such as ACOG and the American College of Medical Genetics and Genomics (ACMG), have been issuing guidelines in an effort to provide support and guidance to obstetrical providers with regard to expanding panels ( Table 1 ). In 2009, ACOG reconfirmed its 2004 committee opinion that AJ carrier testing for 4 disorders (CF, TSD, familial dysautonomia and Canavan disease [CD]) should be offered to any AJ ancestry individual, even if in a mixed relationship, and information about the availability of testing for 5 additional diseases should be provided (Gaucher disease type I [GD], Fanconi anemia group C, Niemann-Pick disease type A, Bloom syndrome, and Mucolipidosis type IV [MLIV]).
| Disease name (abbreviation) | Disease incidence a | Carrier frequency a | Detectability a | Disease characteristics |
|---|---|---|---|---|
| Cystic fibrosis b | 1:2500-1:3000 | 1 per 29 | 97% | Progressive, multisystem disease that primarily affects the pulmonary, pancreatic, and gastrointestinal systems but does not affect intelligence. The current median survival is approximately 37 years, with respiratory failure as the most common cause of death. Approximately 15% of individuals with CF have a mild form of the disease with a median survival of 56 years. More than 95% of males with CF have primary infertility with obstructive azoospermia secondary to congenital bilateral absence of the vas deferens. It is caused by mutations in the CF transmembrane regulator ( CFTR ) gene, located on chromosome 7. |
| Tay-Sachs disease b | 1:3000 | 1 per 30 | 98% by enzyme test, 94% by DNA-based test | Severe, progressive disorder of the central nervous system, leading to death within the first few years of life. Infants with TSD appear normal at birth but by age 5-6 months develop poor muscle tone, have delayed development, have loss of developmental milestones, and develop mental retardation. Children with TSD lose their eyesight at age 12-18 months. This condition usually is fatal by age 6 years. TSD is caused by a deficiency of the hexosaminidase A enzyme. No effective treatment currently is available. |
| Familial dysautonomia b | 1:3600 | 1 per 32 | 99% | Neurological disorder characterized by abnormal suck and feeding difficulties, episodic vomiting, abnormal sweating, pain and temperature insensitivity, labile blood pressure levels, absent tearing, and scoliosis. There currently is no cure for familial dysautonomia, but some treatments that can improve the length and quality of a patient’s life are available. |
| Canavan disease b | 1:6400 | 1 per 40 | 98% | Disorder of the central nervous system characterized by developmental delay, hypotonia, large head, seizures, blindness, and gastrointestinal reflux. Most children die within the first several years of life. Canavan disease is caused by a deficiency of the aspartoacylase enzyme. No treatment currently is available. |
| Gaucher disease type I | 1:900 | 1 per 15 | 95% | Genetic disorder that mainly affects the spleen, liver, and bones; it occasionally affects the lungs, kidneys, and brain. It may develop at any age. Some individuals are chronically ill, some are moderately affected, and others are so mildly affected that they may not know that they have Gaucher disease. The most common symptom is chronic fatigue caused by anemia. Patients may experience easy bruising, nosebleeds, bleeding gums, and prolonged and heavy bleeding with their menses and after childbirth. Other symptoms include an enlarged liver and spleen, osteoporosis, and bone and joint pain. Gaucher disease is caused by the deficiency of the β-glucosidase enzyme. Treatment is available through enzyme therapy, which results in a vastly improved quality of life. |
| Mucolypidosis type IV | 1:62,500 | 1 per 127 | 95% | Neurodegenerative lysosomal storage disorder characterized by growth and psychomotor retardation, corneal clouding, progressive retinal degeneration, and strabismus. Most affected infants never speak, walk, or develop beyond the level of a 1-2 year old. Life expectancy may be normal, and there currently is no effective treatment. |
| Fanconi anemia group C | 1:32,000 | 1 per 89 | 99% | Usually presents with severe anemia that progresses to pancytopenia, developmental delay, and failure to thrive. Congenital anomalies are not uncommon, including limb, cardiac, and genital-urinary defects. Microcephaly and mental retardation may be present. Children are at increased risk for leukemia. Some children have been successfully treated with bone marrow transplantation. Life expectancy is 8-12 years. |
| Niemann-Pick disease type A | 1:32,000 | 1 per 90 | 95% | Lysosomal storage disorder typically diagnosed in infancy and marked by a rapid neurodegenerative course similar to TSD. Affected children die by age 3-5 years. Niemann-Pick disease type A is caused by a deficiency of the sphingomyelinase enzyme. There currently is no treatment. |
| Bloom syndrome | 1:40,000 | 1 per 100 | 95 to 97% | Genetic condition associated with increased chromosome breakage, a predisposition to infections and malignancies, prenatal and postnatal growth deficiency, skin findings (such as facial telangiectasias or abnormal pigmentation), and in some cases learning difficulties and mental retardation. The mean age of death is 27 years and usually is related to cancer. No effective treatment currently is available. |
a When disease incidence data are limited, it can be derived by squaring the carrier frequency (frequency of at risk couples) and multiplying the result by one-fourth (risk for each pregnancy for a carrier couple)
The main determinants in disease selection were the high prevalence of carriers in the population, the severity of the conditions, and the sensitivity of the available tests to detect most carriers. The ACOG guidelines acknowledged that, although testing is also available for the other 5 disorders, given their sometimes lower carrier frequency (eg, MLIV) or lower severity (GD), they would not be included in the recommended panel but rather that information and/or genetic counseling should be made available to support informed decision making. Importantly, it was also recommended that, for the less common disorders, testing should be offered in the event that family history assessment indicates a higher carrier risk.
In 2008, following a conference involving medical professionals and Jewish community groups, the ACMG issued a recommendation that carrier screening should be offered for 9 disorders ( Table 1 ) to individuals who self-identify as of AJ ancestry or who have at least 1 grandparent of AJ ancestry, regardless of the background of their reproductive partner. Despite the lower carrier frequency for some of these diseases and despite the undetermined carrier frequency and detection rate for individuals with less than 100% AJ ancestry, the significant severity of these diseases, the high test efficiency, and/or community preference were considered sufficient to support such recommendations. Furthermore, recommendations were issued for adding conditions to the panel in the future.
If a disorder were to be added, there should be a good understanding of its natural history and it should be severe, and the carrier rate should be at least 1% in the AJ population, or the detection rate of the tests available should be more than 90%. Although severity and underlying genetics of a particular disorder are still critical, the dependence on strict criteria related to carrier and detection rates have been reconsidered by the ACMG because increased mutation detection can now occur with greater speed and fidelity at significantly reduced cost (eg, by technologies such as multiplex arrays or next-generation sequencing). These technologies allow for interrogation of a greater number of mutations across a larger number of recessive conditions, simultaneously.
Currently available testing panels: facts on the ground
In spite of ACOG reissuance of its former recommendations in a revised Committee Opinion in October 2009, several laboratories and community-based screening programs currently are offering carrier screening tests for more than 9 diseases. Many of these panels include up to 18 diseases that have AJ founder mutations and still relatively high carrier rates in the AJ population, taking advantage of new technologies ( Table 2 ). Spinal muscular atrophy, which is not specifically an AJ disease but rather a pan-ethnic condition, is also often offered at the same time.
| Disease name (abbreviation) | Disease incidence | Carrier frequency | Detectability | Disease characteristics |
|---|---|---|---|---|
| Glycogen storage disease type Ia | 1:16,384 | 1 per 64 | 95% | Severe metabolic disorder that is fatal in early childhood if untreated. Close surveyed carbon hydrate dietetic management started at the first days of life allow survival to adulthood, although with severe metabolic risks throughout life. Hepatic dysfunction and liver tumors may occur later in life. Caused by a deficiency of the glycogen-metabolizing enzyme glucose-6-phosphatase. |
| Familial hyperinsulinism | 1:18,496 | 1 per 68 | 90% | Disorder that results from the overproduction of insulin, causing hypoglycemia, which may have severe chronic neurological consequences if unrecognized and not treated in a timely manner. It requires long-term monitoring of glycemia and strict dietetic control. Severity may be variable and in some individuals may be even asymptomatic. Severity is not predictable based on genetic testing. |
| Maple syrup urine disease type 1B | 1:37,636 | 1 per 97 | 95% | Severe metabolic disorder that can lead to neonatal death or neurodevelopmental damage if treatment is not started early in postnatal period. It requires long-term strict dietetic management and monitoring. Even with treatment it can cause neurological and behavioral symptoms of variable severity. It results from the deficiency in an enzyme involved in the metabolism of branched-chain amino acids. The increase in isoleucine, 1 of the amino acids, in urine gives it the odor that gave the disease its name. |
| Dihydro lipoamide dehydrgenase deficiency | 1:45,796 | 1 per 107 | >95% | Disease of variable severity characterized by episodes of lactic acidosis, which may result in severe permanent neurological damage if untreated, usually associated with exercise. If of neonatal onset, it usually results in severe neurodevelopmental consequences and can lead to death, despite treatment. It requires close monitoring throughout life and strict dietary control. It is caused by a deficiency of a mitochondrial enzyme, lipoamide dehydrogenase, which is required for energy production. |
| Usher syndrome type 3 | 1:57,600 | 1 per 120 | >95% | Usher syndrome is a combination of neurosensorial deafness and progressive blindness caused by a retina degenerative disorder, retinitis pigmentosa. In type 3, deafness usually starts in childhood, after speech acquisition, and it is progressive. The visual loss may follow or precede the hearing loss. It is caused by a deficiency in a protein found in the cochlea and retina whose function is still unknown. |
| Usher syndrome type 1F | 1:86,436 | 1 per 147 | ≥75% | In Usher syndrome type 1, the deafness is congenital and the visual loss occurs in the early teens. It also affects the vestibular function, having an impact on the ability to walk. It is caused, in the AJ population, by a defect in a protein–protocadherin-15, which is present in cilia and brain cells. |
| Nemaline myopathy type 2 | 1:112,896 | 1 per 168 | >95% | Mild to moderate myopathy characterized by hypotonia and weakness of the muscles of the face, neck, upper arm, and thighs. It may affect breathing, leading to aspiration pneumonia, difficulty in speech, and difficult feeding. It is caused by a defect in nebulin, a muscle protein. |
| Joubert syndrome type II | 1:33,856 | 1 per 92 | Not enough data | Severe neurological condition with developmental delay and symptoms resulting from cerebellar dysfunction: hyperpnea, hypotonia, ataxia, and ocular apraxia. It can cause kidney failure and affect vision. It results, in the AJ population, from a mutation in a gene, TMEM216 , whose function is still poorly understood. |
| Walker-Warburg syndrome | 1:90,000 | 1 per 150 | Not enough data | Severe neuromuscular and eye disorder |
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