Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze.

Clinical Opinion 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55

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GENETICS

Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze Q7

Jose Carlos P. Ferreira, MD, PhD; Nicole Schreiber-Agus, PhD; Suzanne M. Carter, CGC, JD; Susan Klugman, MD; Anthony R. Gregg, MD; Susan J. Gross, MD

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ecently published data from the 1000 Genomes Project suggest that everyone carries approximately 50-100 variants previously implicated in inherited disorders.1 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 Q1 From the Departments of Obstetrics and

Gynecology and Women’s Health (Drs Ferreira, Klugman, and Gross) and Genetics (Dr Schreiber-Agus), Albert Einstein College of Medicine, Bronx, NY; the Law Offices of Suzanne M. Carter, Englewood, NJ (Ms Carter); and Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville FL(Dr Gregg). Received Oct. 16, 2013; revised Dec. 17, 2013; accepted Feb. 3, 2014. Dr Gross is the Chief Medical Officer of Natera. The other authors report no conflict of interest. Reprints not available from the authors. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.02.001

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. Key words: Ashkenazi Jewish, genetic screening, genomic medicine, preconception care, prenatal testing

(AJ) population.2 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).3

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 wellknown 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

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Genetics

TABLE 1

Disorders for which screening is recommended by the ACOG and/or ACMG Disease name (abbreviation)

Disease incidencea

Carrier frequencya

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 diseaseb

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 dysautonomiab

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 diseaseb

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 b-glucosidase enzyme. Treatment is available through enzyme therapy, which results in a vastly improved quality of life.

Cystic fibrosis

b

Detectabilitya

Disease characteristics

Ferreira. Carrier testing for the Ashkenazi Jewish population. Am J Obstet Gynecol 2014.

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.

(continued)

This mechanism is not unique to the AJ population and explains why TSD is also frequent in the French Québécois

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Clinical Opinion

279 280 TABLE 1 281 Disorders for which screening is recommended by the ACOG and/or ACMG (continued) 282 Disease name Disease Carrier 283 (abbreviation) incidencea frequencya Detectabilitya Disease characteristics 284 Mucolypidosis type IV 1:62,500 1 per 127 95% Neurodegenerative lysosomal storage disorder 285 characterized by growth and psychomotor retardation, 286 corneal clouding, progressive retinal degeneration, and 287 strabismus. Most affected infants never speak, walk, 288 or develop beyond the level of a 1-2 year old. Life expectancy may be normal, and there currently is no 289 effective treatment. 290 Fanconi anemia 1:32,000 1 per 89 99% Usually presents with severe anemia that progresses to 291 group C pancytopenia, developmental delay, and failure to 292 thrive. Congenital anomalies are not uncommon, 293 including limb, cardiac, and genital-urinary defects. 294 Microcephaly and mental retardation may be present. 295 Children are at increased risk for leukemia. Some children have been successfully treated with bone 296 marrow transplantation. Life expectancy is 8-12 years. 297 298 Niemann-Pick 1:32,000 1 per 90 95% Lysosomal storage disorder typically diagnosed in disease type A infancy and marked by a rapid neurodegenerative 299 course similar to TSD. Affected children die by age 3-5 300 years. Niemann-Pick disease type A is caused by a 301 deficiency of the sphingomyelinase enzyme. There 302 currently is no treatment. 303 Bloom syndrome 1:40,000 1 per 100 95 to 97% Genetic condition associated with increased 304 chromosome breakage, a predisposition to infections 305 and malignancies, prenatal and postnatal growth 306 deficiency, skin findings (such as facial telangiectasias or abnormal pigmentation), and in some cases learning 307 difficulties and mental retardation. The mean age of 308 death is 27 years and usually is related to cancer. No 309 effective treatment currently is available. 310 Carrier frequency is calculated as the ratio between the number of carriers and the number of individuals tested. Detectability refers to the percentage of carriers with recessive mutations in a given 311 gene that are detected by the test. It is based on the proportion of the abnormal alleles that are detected by the test in the population of affected individuals. These data may vary with studied population. 312 ACMG, American College of Medical Genetics; ACOG, American College of Obstetricians and Gynecologists; CF, cystic fibrosis; TSD, Tay-Sachs disease. 313 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 314 carrier couple); b ACOG-recommended disorders. 315 Adapted, with permission, from ACOG recommendations. 316 Q5 Ferreira. Carrier testing for the Ashkenazi Jewish population. Am J Obstet Gynecol 2014. 317 318 319 population, who are the descendants of a The difficult choice: what disorders be offered to any AJ ancestry individual, 320 small group of migrants from France. Of should the obstetrician-gynecologist even if in a mixed relationship, and in321 note, the founder mutations for this provider offer to AJ individuals for formation about the availability of 322 population are different from the classic optimal carrier screening? testing for 5 additional diseases should 323 AJ Tay-Sachs mutations. be provided (Gaucher disease type I Professional recommendations 324 In the last decades, in part because of Professional societies, such as ACOG [GD], Fanconi anemia group C, 325 the Human Genome Project, the causal and the American College of Medical Niemann-Pick disease type A, Bloom 326 genes identified and the number of dis- Genetics and Genomics (ACMG), have syndrome, and Mucolipidosis type IV 327 4 eases for which carrier screening is been issuing guidelines in an effort to [MLIV]). 328 available has progressed far beyond TSD, provide support and guidance to The main determinants in disease se329 and this trend is expected to continue. obstetrical providers with regard to lection were the high prevalence of car330 Paradoxically, as is often the case with expanding panels (Table 1). In 2009, riers in the population, the severity of the ½T1 331 technological breakthroughs, such de- ACOG reconfirmed its 2004 committee conditions, and the sensitivity of the 332 velopments can be a source of uncer- opinion that AJ carrier testing for 4 available tests to detect most carriers. The 333 tainty as well as a welcomed benefit to disorders (CF, TSD, familial dysautono- ACOG guidelines acknowledged that, 334 both providers and patients. mia and Canavan disease [CD]) should although testing is also available for the MONTH 2014 American Journal of Obstetrics & Gynecology FLA 5.2.0 DTD YMOB9667_proof 5 May 2014 10:28 pm ce

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Genetics

TABLE 2

Other disorders for which carrier screening may be available Disease name (abbreviation)

Disease incidence

Carrier frequency

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 longterm 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 aminoacids. The increase in isoleucine, 1 of the amino acidsd, 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 proteineprotocadherin-15, which is present in cilia and brain cells.

Detectability

Disease characteristics

Ferreira. Carrier testing for the Ashkenazi Jewish population. Am J Obstet Gynecol 2014.

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

(continued)

that, for the less common disorders, testing should be offered in the event that family history assessment indicates a higher carrier risk.


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Clinical Opinion

503 504 TABLE 2 505 Other disorders for which carrier screening may be available (continued) 506 Disease name Disease Carrier 507 (abbreviation) incidence frequency Detectability Disease characteristics 508 Nemaline myopathy 1:112,896 1 per 168 >95% Mild to moderate myopathy characterized by hypotonia 509 type 2 and weakness of the muscles of the face, neck, upper 510 arm, and thighs. It may affect breathing, leading to 511 aspiration pneumonia, difficulty in speech, and difficult 512 feeding. It is caused by a defect in nebulin, a muscle protein. 513 514 Joubert syndrome type II 1:33,856 1 per 92 Not enough data Severe neurological condition with developmental delay and symptoms resulting from cerebellar 515 dysfunction: hyperpnea, hypotonia, ataxia, and ocular 516 apraxia. It can cause kidney failure and affect vision. It 517 results, in the AJ population, from a mutation in a gene, 518 TMEM216, whose function is still poorly understood. 519 Walker-Warburg syndrome 1:90,000 1 per 150 Not enough data Severe neuromuscular and eye disorder 520 For most disorders listed, data were obtained from Scott et al7; data for Joubert syndrome type II were obtained from Edvarson et al (2010) and for Walker-Warburg syndrome from Chung et al (2009). Q6 521 The frequencies and detectability presented here refer to individuals in which both parents are of Ashkenazi Jewish ancestry. 522 Ferreira. Carrier testing for the Ashkenazi Jewish population. Am J Obstet Gynecol 2014. 523 524 525 In 2008, following a conference greater speed and fidelity at significantly statement.6 Of note, whereas the carrier 526 involving medical professionals and reduced cost (eg, by technologies such rate calculations have good supporting 527 Jewish community groups, the ACMG as multiplex arrays or next-generation evidence based on data provided by large 528 issued a recommendation that carrier sequencing).6 These technologies allow sample-size studies,7 the same cannot 529 screening should be offered for 9 disor- for interrogation of a greater number of be said for detection rate calculations. 530 ders (Table 1) to individuals who self- mutations across a larger number of Given the fact that detection rate is based 531 identify as of AJ ancestry or who have recessive conditions, simultaneously. on data collected from affected in532 at least 1 grandparent of AJ ancestry, dividuals and given the rarity of several 533 regardless of the background of their Currently available testing panels: facts of the diseases for which carrier testing is 534 reproductive partner.5 Despite the lower on the ground offered, the sample size of the studies 535 carrier frequency for some of these In spite of ACOG reissuance of its providing data for this calculation may 536 diseases and despite the undetermined former recommendations in a revised be quite small, resulting in very wide 537 carrier frequency and detection rate Committee Opinion in October 2009,4 confidence intervals. 538 Such potential errors in the estimate for individuals with less than 100% AJ several laboratories and community539 ancestry, the significant severity of these based screening programs currently are of the precise detection rate may greatly 540 diseases, the high test efficiency, and/or offering carrier screening tests for more affect the residual risk calculation, 541 community preference were considered than 9 diseases. Many of these panels which is the chance that there still may 542 sufficient to support such recommenda- include up to 18 diseases that have AJ be risk, even if a screening test returns as 543 tions. Furthermore, recommendations founder mutations and still relatively negative. Thus, the suboptimal data on 544 were issued for adding conditions to the high carrier rates in the AJ population, the detection rate make the negative 545 panel in the future. taking advantage of new technologies predictive value (the probability of not 546 If a disorder were to be added, there (Table 2). Spinal muscular atrophy, being a carrier if the test is negative) ½T2547 should be a good understanding of its which is not specifically an AJ disease difficult to determine. Conversely, the 548 natural history and it should be severe, but rather a pan-ethnic condition, is specificity of deoxyribonucleic acid 549 (DNA)-based tests is quite high, resultand the carrier rate should be at least also often offered at the same time. 550 1% in the AJ population, or the detecMany, but not all, disorders that have ing in an extremely low false-positive 551 tion rate of the tests available should be been progressively added to the panels rate. In disorders and populations in 552 more than 90%.5 Although severity and do fit the original criteria proposed by which the carrier frequencies are quite 553 underlying genetics of a particular dis- the ACMG5 such that severity remains high (higher than 1:100), the positive 554 order are still critical, the dependence an important consideration. However, predictive value (the possibility of being 555 on strict criteria related to carrier and there is movement away from the nu- a carrier if the test is positive) is close to 556 detection rates have been reconsidered merical constraints of detection rate 100% and not significantly changed by 557 by the ACMG because increased mu- and allele frequency thresholds more in the relatively smaller carrier rate in in558 tation detection can now occur with keeping with the new ACMG policy dividuals with only 1 grandparent of MONTH 2014 American Journal of Obstetrics & Gynecology FLA 5.2.0 DTD YMOB9667_proof 5 May 2014 10:28 pm ce

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Genetics

TABLE 3

Key points for the practicing obstetric provider 1. Discuss family history, ethnicity, and preconception/prenatal testing options with all patients. 2. Provide counseling about carrier screening to all individuals of AJ descent; make sure you discuss different testing options and that the patient is made aware that it is a screening test and that a negative test still implies a residual risk. 3. Document that you have provided counseling, whether or not the patient agrees to testing, and that consent for testing, preferably in writing, was obtained. 4. In mixed-ancestry couples, test the AJ individual first. See number 7 below if that individual is positive. 5. Always include Tay-Sachs enzyme testing when screening for TSD, especially with individuals of questionable AJ ancestry. 6. Provide or make available posttest genetic counseling for carriers. 7. If 1 member of a couple is a carrier, fully screen the other member of the couple (ie, for all AJ mutations, and also consider DNA sequencing, if appropriate). 8. Carefully review test results, including residual risk and provide patients with copies. 9. Consider using standardized checklists or handouts and develop follow-up procedures for referrals and/or test results. 10. Discuss carrier screening with each pregnancy, preferably prior to conception, because testing is rapidly evolving and previous test results may need updating. AJ, Ashkenazi Jewish; TSD, Tay-Sachs disease. Ferreira. Carrier testing for the Ashkenazi Jewish population. Am J Obstet Gynecol 2014.

AJ ancestry. When carrier frequencies become increasingly low, the positive predictive value will drop as well. Furthermore, the diversity of the test panels being offered to patients, made available at the discretion of each laboratory and provider, raises several important issues relating to expanded carrier screening that are outlined in the following text.

Ethical issues Equal access is a fundamental principle when assessing the ethics of population screening programs, particularly when public funding is involved.8 Because the decision about which disorders to test for has been at the discretion of each laboratory/provider, the equality of access to the most complete panel may be somewhat compromised. However, all medical innovations have a period during which they may not be universally accessible and thus undergo a time frame early on, which is not ethically just. Once the advance is proven to be of benefit to most, a professional endorsement will be forthcoming, which usually allows for more equal access. Moreover, as panels expand, how can appropriate ethical informed consent be

provided? The inclusion of more conditions on a panel increases the complexity of the pretest counseling and education. Not all diseases on the larger panels are equivalent with respect to severity, carrier rate, or detection rates. Clearly, consenting for multiple conditions is time consuming and difficult and will only become more difficult as panels are further expanded. The patient should be made aware of the inheritance of these disorders and that these conditions are offered in a screening panel because these conditions have the potential for severe morbidity and mortality in childhood. We have found it helpful to provide patients with literature, ideally professionally prepared. In addition, as we move closer to technologies that will allow for genome/exome sequencing to be used for carrier screening, we will need to grapple with variants of uncertain significance and incidental findings. How to handle and report these findings has become a major focus within the genetics professional community, with implications well beyond the AJ population. Presently ACOG recommends that personalized genome/exome testing not be used beyond clinical trials until

clinical utility and prospective studies are available.9

Economic concerns and costeffectiveness Although a thorough exploration of cost-effectiveness is beyond the scope of this paper, there are certain basic principles that maintain an important place in any public health policy discussion related to screening programs. Both the ACOG and ACMG recommendations take into account an economic evaluation that contrasts the costs against the benefits associated with the AJ carrier screening program. However, although newer technologies continue to force down prices, cost analyses must include other expenses such as the cost of genetic counseling (and ultimately bioinformatics as well). In addition to the pretest counseling mentioned in the previous text, the higher the number of the tested disorders, the higher the number of carriers requiring posttest counseling. It is estimated that going from a 9 to 16 disease panel causes the frequency of individuals testing positive to increase from 1 in 5 to 1 in 3.7 Although the number of individuals requiring posttest counseling will almost double, the number of additional affected individuals detected will increase at a slower rate because of the rarity of many of these disorders. Thus, the relative cost of each detected affected individual, if we factor in the costs of counseling, may actually be higher. Whereas cost considerations are based on public health models in which the overall health care funding for a general population must be taken into account, for the AJ population, it should be noted that philanthropic organizations have developed around its carrier testing whereby the community itself absorbs some of the financial burden. Going forward, as large scale testing becomes even more affordable, it may be not only ethical, but more cost effective, to offer patients the opportunity to undergo carrier screening for a large set of rare diseases.6 Furthermore, pan-ethnic (universal) expanded panels may benefit those patients of mixed or


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Genetics

unknown ethnicity, which is an evergrowing reality in the United States, particularly when patients are asked to self-identify as 1 particular race or ethnicity. It is even likely that in a more distant future, whole-exome and even wholegenome sequencing will eventually be promoted for this type of use. However, concerns remain that variants of unknown significance will remain an important concern because it has an impact on the false-positive rate. Furthermore, it is important to note that the carrier rate of the mutations responsible for non-Jewish genetic disorders, present in the expanded panels, is relatively much lower in AJ and non-AJ or mixed populations, resulting in a much lower efficiency of carrier screening in ethnically diverse populations with a relatively small added benefit to the AJ population. Professional bodies are currently addressing these very issues, which will hopefully result in a more uniform approach or preferably a consensus to expanded carrier screening panels.

Q4

Liability issues ACOG recommends that obstetrical providers ensure that all women undergo a family history evaluation for genetic risk assessment, which includes ethnic predisposition.10 Providers who fail to provide or recommend genetic counseling and/or testing can be liable for the birth of a child with impairment if proper genetic screening or diagnosis was not made available. Generally, this is known as wrongful birth claims (see for example Geler v. Akawie, 358 N.J. Super. 437, 818 A.2d 402 [App.Div. 2003]). Likewise, liability may be imposed on a physician for failing to make a correct diagnosis, not obtaining informed consent, and disclosing results to persons other than the person screened. ACOG has addressed these issues in Committee Opinion no. 410.11 The obstetrician-gynecologist who ordered the test is required to educate the patient about implications for the family as a whole (ie, blood relatives) and “why voluntary disclosure would in many

circumstances be encouraged (as well as the possibility that relatives might prefer not to know the results).” If the patient agrees to testing, then the consent should preferably be in writing because oral consent may not be sufficient protection in legal settings. In fact, many states require written consent for genetic testing, and these consent forms will contain the statutorily required elements of informed consent. For states that do not require written consent, written consent forms for genetic testing are usually regulated by professional bodies. Additionally, forms provided by the laboratory in which testing is performed can be used as long as they conform to the requirements of regulatory bodies. Questions remain such as to whether liability arises when a child is born with a disorder for which screening was readily available but not included in the current ACOG guidelines. The answer is maybe. Standard of care generally includes reference to an obstetrician-gynecologist’s judgment in a given clinical circumstance. An expert will have to establish not what should have been done but instead what was actually being done at the time the obstetrician-gynecologist was doing the AJ screening. Liability will often hinge on who wins the battle of experts and whether community or national standards of care are followed in the jurisdiction. It cannot be overstated that the best protection is for the obstetrician-gynecologist generalist to participate in continuing medical education and to assess his or her own qualifications for follow-up as well as to develop the appropriate referral mechanisms to ensure the best care possible.

Current recommendations Currently, at the very least, all 4 ACOGrecommended disorders (TSD, Canavan disease, CF, and familial dysautonomia) must be offered to all individuals of AJ descent (defined as having 1 AJ grandparent) who are considering a pregnancy or are currently pregnant and have not yet had this testing done. TSD carrier status should also be assessed

Clinical Opinion

727 using hexosaminidase enzymatic activ728 ity testing (ie, not only by DNA testing) 729 because the enzyme assay detects all 730 carriers, regardless of ethnicity.12,13 731 Because of demographic and cultural 732 changes, the AJ community is no longer 733 as homogenous as it once was, to the 734 extent that up to 10% of individuals who 735 self-identify as Jews could be falsely 736 labeled as screen negative, using targeted 737 DNA mutation testing rather than 738 enzyme analysis.14 Using the ACMG 739 criteria, Niemann-Pick disease type A, 740 MLIV, GD, Fanconi anemia group C, 741 and Bloom syndrome should also be 742 included as a minimum. Because ex743 tended panels are already becoming 744 available, assuming that counseling is 745 provided and informed consent is ob746 tained, and that all regulatory laboratory 747 benchmarks are met, this additional 748 testing can be explained and offered 749 (Table 3). ½T3 750

Summary and conclusions As long as the genetic tests under consideration for inclusion meet professional society criteria and there is sufficient financial support behind not only the tests but also associated counseling, expansion of current testing panels in the AJ community is to be expected. It is thus crucial that the provider keep apprised of current screening recommendations and that patients receive a copy of their test results. It is also important for the professional community to remember the objective of such screening programs, which is to promote health, and the centrality of informed decision making. REFERENCES 1. Consortium GP, Abecasis GR, Altshuler D, et al. A map of human genome variation from population-scale sequencing. Nature 2010;467: 1061-73. 2. Kaback MM. Population-based genetic screening for reproductive counseling: the TaySachs disease model. Eur J Pediatr 2000;159(Suppl 3):S192-5. 3. American College of Obstetricians and Gynecologists. Update on carrier screening for cystic fibrosis. ACOG Committee Opinion no. 486. Obstet Gynecol 2011;117:1028-31. 4. American College of Obstetricians and Gynecologists. Preconception and prenatal carrier

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Genetics

screening for genetic diseases in individuals of Eastern European Jewish descent. ACOG Committee Opinion no. 442. Obstet Gynecol 2009;114:950-3. 5. Gross SJ, Pletcher BA, Monaghan KG; Professional Guidelines and Practice Committee. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med 2008;10: 54-6. 6. Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med 2013;15:482-3. 7. Scott SA, Edelmann L, Liu L, Luo M, Desnick RJ, Kornreich R. Experience with carrier screening and prenatal diagnosis for 16

Ashkenazi Jewish genetic diseases. Hum Mutat 2010;31:1240-50. 8. Beauchamp TL. Principles of biomedical ethics. 2008:432. 9. American College of Obstetricians and Gynecologists. Personalized genomic testing for disease risk. ACOG Committee Opinion no. 527. Obstet Gynecol 2012;119:1318-9. 10. American College of Obstetricians and Gynecologists. Family history as a risk assessment tool. Committee Opinion no. 478. Obstet Gynecol 2011;117:747-50. 11. American College of Obstetricians and Gynecologists. Ethical issues in genetic testing. ACOG Committee Opinion no. 410. Obstet Gynecol 2008;111:1495-502.

12. NTSAD Position Statement: Tay-Sachs carrier screening. 2009. Available at: http:// www.ntsad.org/index.php/documents/func-do wnload/5/chk,ec07af18673830f267d933c4c1 Q2 bfb4cf/no_html,1/. Accessed June 10, 2013. 13. Kaback MM, Desnick RJ. Hexosaminidase A deficiency. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, eds. Gene reviews. Seattle, WA: 1999 (Updated Aug. 11, Q3 2011). 14. Schneider A, Nakagawa S, Keep R, et al. Population-based Tay-Sachs screening among Ashkenazi Jewish young adults in the 21st century: hexosaminidase A enzyme assay is essential for accurate testing. Am J Med Genet A 2009;149A:2444-7.


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Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.

Expanded genetic screening panel for the Ashkenazi Jewish population.

Interest in genetic testing in Ashkenazi Jewish Parkinson's disease patients and their unaffected relatives.

Knowledge, attitudes, and barriers to carrier screening for the Ashkenazi Jewish panel: a Florida experience : Education and Barriers assessment for Jewish Genetic Diseases.

Creation of a National, At-home Model for Ashkenazi Jewish Carrier Screening.

Hereditary chondrocalcinosis in an Ashkenazi Jewish family.

Navigating the renal stent empirical maze.

2 testing in Ashkenazi Jewish individuals without founder mutations.

Cost-effectiveness of population screening for BRCA mutations in Ashkenazi jewish women compared with family history-based testing.

Prenatal genetic counselling for psychiatric disorders.

Molecular testing for the BRCA1 and BRCA2 Ashkenazi Jewish founder mutations: a report on the College of American Pathologists proficiency testing surveys.

Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene.

Genetic movement disorders in patients of Jewish ancestry.

Prenatal diagnosis of genetic disorders.

Innovations in prenatal genetic testing beyond the fetal karyotype.

Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium.

The time and place of European admixture in Ashkenazi Jewish history.

Diagnostic, carrier and prenatal genetic testing for fragile X syndrome and other FMR-1-related disorders in Johannesburg, South Africa: a 20-year review.

Genetic testing in bleeding disorders.

Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population.

Genetic analysis of cystic fibrosis in Denmark. Implications for genetic counselling, carrier diagnosis and prenatal diagnosis.

Personalized genomic medicine and prenatal genetic testing.

Prenatal genetic testing for familial severe congenital protein C deficiency.

Molecular carrier testing for the fragile X syndrome: Issues for genetic counselors.