Version May 2024
INTRODUCTION — When a pathogenic genetic variant is present in a community that procreates mostly among themselves, the frequency of the variant will become higher in that community compared with the general population and the community will have a higher incidence of rare genetic disorders associated with the variant, a situation known as the "founder effect." The increased incidence of Tay-Sachs disease and several other serious disorders (table 1) in people of Ashkenazi Jewish ancestry is an example of this phenomenon and the reason genetic carrier screening programs have been successful and have had a high acceptance rate in this population [1,2].
This topic will discuss preconception and prenatal screening for disorders that are more common in people of Ashkenazi Jewish ancestry, have an identifiable carrier state, and are serious (ie, severely disabling, untreatable, and associated with a shortened life expectancy). It also addresses management of individuals with a family member with one of the genetic conditions prevalent in people of Ashkenazi Jewish ancestry. The BRCA pathogenic variant, which is also more prevalent in this population, does not meet the latter criteria as the development of breast or ovarian cancer in BRCA carriers is not certain and is potentially preventable and treatable. BRCA founder pathogenic variant screening is reviewed separately. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes", section on 'Population-based testing for those of Ashkenazi Jewish descent'.)
New technologies using DNA sequencing and microarray hybridization analysis allow more comprehensive, general population-based carrier screening for a large number of pathogenic variants. Some commercially available genetic carrier screening tests screen for several hundred genetic diseases (using either saliva or blood) at approximately the same cost as screening for single gene pathogenic variants. The introduction of these new tests has shifted the screening paradigm from the traditional family medical history- or ethnicity-based risk for genetic disease (as in people of Ashkenazi Jewish ancestry) to a population-neutral approach using panethnic expanded carrier screening. Some concerns with the panethnic approach have been the detection of genes with mild phenotypes, variable expression, low penetrance, and/or identifying diseases characterized by adult onset. An advantage of a panethnic- and population-neutral approach is that it may be a more accurate way to ascribe risk given increasing evidence that self-reported ethnicity has inaccuracies, which has the effect of underestimating risk of genetic disease [3]. (See "Preconception and prenatal panethnic expanded carrier screening".)
SCREENING
Rationale for carrier screening — Carrier screening can identify asymptomatic individuals who carry pathogenic variants. If both parents are carriers of a pathogenic variant causing the same disorder, there is a one in four chance that their offspring will inherit two copies of the pathogenic variant (one from each parent) and will be susceptible to developing the phenotype. Identification of these couples gives them the opportunity to become informed about their risks and pursue reproductive options to avoid an affected pregnancy, prepare for the birth of an affected child, or terminate an affected pregnancy. Negative test results relieve some of the anxiety associated with pregnancy. (See 'Posttest counseling and management' below.)
Rationale for screening in individuals of Ashkenazi Jewish descent — One in four to one in five individuals of Ashkenazi Jewish descent (descendants of Jewish people from Central and Eastern Europe [eg, Germany, France, Poland, Hungary, Russia, Ukraine, Lithuania]) carry a pathogenic variant for one of the autosomal recessive disorders included in the specific group of disorders listed in the table (table 1). Most of these disorders are severely disabling, untreatable, and associated with a shortened life expectancy. Some of the disorders (eg, Tay-Sachs disease) have a high incidence primarily among individuals of Ashkenazi Jewish descent, and for many of the disorders (eg, familial dysautonomia), the pathogenic variant has been identified almost exclusively in these individuals [1]. Although the disorders can also affect people of Sephardic Jewish ancestry (descendants of Jewish people from Spain, Portugal, and North Africa), people without Jewish ancestry, and Jewish people from mixed backgrounds, they are less prevalent in these populations.
Laboratories offer carrier screening panels that test for several disorders as a group in a single multiplex assay. The number of disorders included in panels for individuals of Ashkenazi Jewish descent is variable (eg, 4, 9, 11, or more), based in part on the carrier frequency in this population and the severity of the phenotype. Some panels include disorders that are rare even in this population but are included because only a few pathogenic variants account for the majority of disease. Some laboratories offer an Ashkenazi Jewish ethnicity-based panel that includes carrier screening for other autosomal recessive disorders more prevalent in people of Ashkenazi Jewish descent. Routinely screening for Maple Syrup Urine Disease, dihydrolipoamide dehydrogenase deficiency, and Glycogen Storage Disease Type 1a is reasonable since the screening test has a >90 percent detection rate or allele frequency ≥1 percent in people of Ashkenazi Jewish descent and the disorders are associated with significant morbidity and/or mortality.
Screening for autosomal recessive diseases with an allele frequency <1 percent is controversial. While ACOG practice guidelines use an allele frequency threshold of 1 in 100 or greater, ACMG uses a threshold of 1 in 200 [3]. For people of Ashkenazi Jewish descent, diseases with allele frequency between 1 in 100 and 1 in 200 include nemaline myopathy (1 in 120), Usher syndrome type 1F (1 in 165), Usher syndrome type 3 (1 in 107), and Joubert syndrome (1 in 102). Testing for carrier status is indicated if a patient has a family member affected by one of these disorders or known to be a carrier of a gene responsible for one of these disorders and may be considered in all persons of Ashkenazi Jewish descent. Allele frequency for Walker-Warburg syndrome has been reported to be 1 in 150 to 1 in 79 [4]. It is not included among disorders in ACOG practice guidelines for screening in people of Ashkenazi Jewish descent, but if an allele frequency ≥1 percent is used as a threshold for offering carrier screening, then it would be reasonable to offer carrier screening for Walker-Warburg syndrome in people of Ashkenazi Jewish descent.
Strategy
Panethnic approach — The author of this topic uses a panethnic approach for genetic carrier screening consistent with the recommendations of ACMG [3]. ACMG recommends routinely offering panethnic expanded carrier screening for tier 3 conditions to all pregnant patients and those planning a pregnancy [3]. These conditions are described in five tables and consist of autosomal recessive conditions having a carrier frequency ≥1 in 50, 100, 150, or 200 in the general population or a carrier frequency that is highly represented in one or more patient populations (such as Ashkenazi Jewish descendants) and has the potential to be underrepresented in the Genome Aggregation Database (gnomAD) or genes with at least a 1/200 carrier frequency of pathogenic or likely pathogenic variants in a subpopulation that has at least 1 percent representation in the US including US territories. Tier 3 conditions include all 14 conditions more prevalent in Ashkenazi Jewish descendants. (See "Preconception and prenatal panethnic expanded carrier screening".)
Ethnic approach — The ACOG Committee on Genetics recommends routinely offering all people of Ashkenazi Jewish ancestry carrier screening for four of the most common disorders that are either lethal or associated with significant morbidity: Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia, and considers offering an expanded panel an acceptable approach. The expanded panel would include these four disorders plus Bloom Syndrome, familial hyperinsulinism, Fanconi anemia group C, Gaucher disease, glycogen storage disease type I, Joubert syndrome, maple syrup urine disease, mucolipidosis IV, Niemann Pick disease type A, and Usher syndrome [5]. In addition, ACOG recommends offering spinal muscular atrophy carrier screening to all pregnant people or people planning pregnancy, regardless of race or ethnicity [5]. (See "Spinal muscular atrophy".)
With this approach, the following is advised to identify candidates:
●Review the personal and family history of individuals considering pregnancy or who are already pregnant to determine whether either member of the couple is of Ashkenazi Jewish ancestry or has a relative with one or more genetic disorders more prevalent in this population (table 1).
●Offer carrier screening to:
•Individuals of Ashkenazi Jewish descent – One grandparent of Ashkenazi Jewish descent is sufficient to justify testing. If Ashkenazi Jewish ancestry is more remote, it is still prudent to offer screening, but patients should understand that carrier screening has variable sensitivity and specificity in the setting of mixed ancestry because the frequencies and known pathogenic variants of most of these diseases are less well established.
•Individuals unsure of their Ashkenazi Jewish ancestry.
•Individuals with a relative with one of the genetic conditions in the table (table 1)
-Individuals with an affected first-degree relative (parent, sibling, child) or second-degree relative (aunt/uncle, niece/nephew, grandparent, half-sibling) are at high risk of being a carrier. This risk can be 33 to 100 percent, depending upon which relative is affected.
-Whether to screen patients with a more remote family history of disease is controversial. As an example, if a fifth-degree relative (eg, second cousin) is known to have been affected with one of the diseases of concern, a patient has a 1 in 16 chance of being a carrier and this risk is higher than the carrier frequencies of most of the genetic diseases in people of Ashkenazi Jewish descent. Therefore, we believe any history of a blood relative with a confirmed autosomal recessive disease justifies offering carrier testing.
•Partners of individuals who are screen-positive, whether or not they are of Ashkenazi Jewish descent.
Consent — Screening programs should be voluntary, confidential, and with informed consent. If a screening panel is ordered, the patient should be informed about and consent to all the diseases included in the panel. If a patient requests screening only for a particular condition for which testing is available, the requested test should be offered [5].
It may not be practical for a clinician to discuss each disease included in a multi-disease carrier screening panel. The ACMG suggests giving patients an informational pamphlet or referring them to an internet site where they can obtain a brief description of each disorder included in the test panel. Genetic counseling before testing should be available for patients who want more information [3].
Timing and testing sequence
●Before conception – Ideally, carrier testing of either partner of an Ashkenazi Jewish couple is initiated at a preconception counseling visit. If that partner tests positive, carrier testing can then be extended to the other partner (ie, sequential testing). If testing is negative, the other partner is not tested.
When only one partner is of Ashkenazi Jewish descent, that partner should be screened first [6].
●During pregnancy – If the patient is already pregnant and only one partner is of Ashkenazi Jewish descent, that partner should be screened first. However, carrier testing of both partners can also be performed simultaneously at the first prenatal visit. Screening results are typically available in one to two weeks. This should allow ample time for further prenatal evaluation and diagnosis in the event that both partners screen positive.
Test requisition — Carrier testing for each disease generally involves DNA sequencing for that disease. There are many different pathogenic variants associated with the various diseases; thus, the test requisition typically states "DNA sequencing for" and then lists the diseases/syndromes for which the patient has consented to be screened (eg, Tay-Sachs, Bloom, cystic fibrosis) rather than a specific pathogenic variant.
An exception is Tay-Sachs screening. In this case, biochemical analysis is preferred as the primary testing method because it is more sensitive than DNA sequencing [7]. In people of Ashkenazi Jewish descent, biochemical screening for hexosaminidase A activity detects 97 to 98 percent of carriers compared with 93 to 95 percent of carriers with DNA sequencing that tests for the three common pathogenic variants accounting for >95 percent of disease alleles in this population (1278insTATC, G269S, 1421+1GC) [8]. In low-risk populations, biochemical analysis identifies 87 to 92 percent of carriers, while DNA sequencing may identify only 46 percent of carriers [9]. (See 'Tay-Sachs disease' below.)
Posttest counseling and management — Posttest genetic counseling should be available for those with positive screening results and can also be helpful for those with negative results [3]. Posttest counseling should include test results for the patient and/or partner, a discussion of the risk to any current or future pregnancy, and a discussion of residual risk after testing. For example, the residual risk that the adult is a carrier after a negative test result in an individual of full Ashkenazi Jewish descent is 1/400 for cystic fibrosis, 1/2700 for Tay-Sachs disease, 1/2500 for Canavan disease, and 1/4900 for familial dysautonomia [8]. It should be noted, however, that DNA sequencing has lower sensitivity in people of Ashkenazi Jewish descent, so residual risk may be higher.
If the carrier is pregnant and the partner is not available for testing, the risk of fetal disease can be estimated based on the carrier rate in the partner's ethnic group, and options for fetal diagnosis should be discussed.
Both partners positive — If both parents are carriers, each offspring has a 25 percent chance of inheriting the disease, a 50 percent chance of being a carrier, and a 25 percent chance of not inheriting the affected allele. Posttest counseling should include an explanation of the pathogenic variant(s) detected; risk of disease; clinical manifestations, range of severity, natural history, and management of the disorder; options for fetal testing and reproductive decision making; and implications for other family members at risk for the disorder [3]. This discussion is made easier by appropriate pretest counseling, during which many of these issues will have been introduced. When an individual is found to be a carrier, his or her relatives are also at risk for carrying the same pathogenic variant; the individual should be encouraged to discuss this information with them.
When carrier pathogenic variants are identified preconceptionally in both parents, they may choose to avoid pregnancy, use gametes from a donor who is a noncarrier, use preimplantation genetic testing with transfer of only unaffected embryos, or conceive naturally and undergo prenatal diagnosis if desired.
If pregnancy is already established, fetal DNA sequencing can be performed on chorionic villi at 10 to 14 weeks of gestation or on amniocytes/amniotic fluid at ≥15 weeks of gestation (see "Chorionic villus sampling" and "Diagnostic amniocentesis"). Techniques for detecting such single-gene disorders by a noninvasive maternal blood sampling are being developed. (See "Cell-free DNA screening for fetal conditions other than the common aneuploidies", section on 'Screening for monogenic disease'.)
Pregnancy termination is an option, if desired.
One or both partners negative — Genetic counseling should inform the couple of the residual risk for the disease. A negative screening test result for one or both partners significantly reduces the possibility of an affected offspring, but does not exclude it because not all pathogenic variants are known or included on the test and therefore not every carrier is identified. Sequencing approaches of the candidate genes will increase detection of pathogenic variants as well as variants of unknown significance.
Both partners negative — When both partners screen negative for carrier pathogenic variants, they should be counseled that the risk for an affected child is very low but not zero. As an example, if both partners are of Ashkenazi Jewish descent and they test negative for Tay-Sachs using DNA sequencing, the residual risk of having an affected fetus is <1 in 1,000,000 [8].
One partner positive and the other negative — If both partners are of Ashkenazi Jewish descent and one tests positive as a carrier and the other tests negative, the residual risk of having an affected fetus depends on the carrier rate of the disease in people of Ashkenazi Jewish descent and the detection rate of the screening test for the disease. As examples, the residual risk that the fetus is affected is 1 in 6200 for Canavan disease, 1 in 11,000 for Tay-Sachs disease (using DNA sequencing), and 1 in 20,000 for familial dysautonomia [8]. Given the extremely low residual risk, no further testing is generally advised.
SYNOPSIS OF DISORDERS IN THE FOURTEEN-DISORDER ASHKENAZI SCREENING PANEL
Bloom syndrome — Bloom syndrome is an autosomal recessive chromosome instability disorder.
Epidemiology — The syndrome is extremely rare in the general population. In people of Ashkenazi Jewish descent , however, the carrier frequency is 1/102 and the disease incidence is 1/48,000 [10-12]. One-third of affected individuals are of Ashkenazi Jewish descent [13].
Clinical features — Clinical features of Bloom syndrome include:
●Small stature
●Predisposition to the early development of a wide variety of cancers
●Facial anomalies and sun-sensitive facial erythema
●Infertility
●Immunodeficiency
●Restricted intellectual ability
●Predisposition to develop late-onset non-insulin dependent diabetes mellitus
The clinical features are believed to be the result of increased chromosome breakage and sister chromatid exchange. The mean age of death in patients with Bloom syndrome is 28 years (range 4 to 46 years) [13]. The cause of death is usually cancer, commonly leukemia or a malignancy of gastrointestinal origin. (See "Bloom syndrome".)
Testing — In people of Ashkenazi Jewish descent , almost all of those with Bloom syndrome are homozygous for a complex frameshift variant (6-bp deletion/7-bp insertion at BLM nucleotide 2281) blmAsh. Carrier testing for this pathogenic variant is estimated to detect 95 to 97 percent of carriers in this population [11].
Canavan disease — Canavan disease is a neurodegenerative disease characterized by leukodystrophy and spongy degeneration of the brain. It is caused by a deficiency of the enzyme aspartoacylase (ASPA), which leads to increased N-acetylaspartic acid (NAA) levels in brain and urine. NAA is an amino acid normally abundant in the brain and is second only to glutamate in the free amino acid pool [14]. Its role is unclear, but NAA may be involved in myelin synthesis.
Epidemiology — One in 40 people of Ashkenazi Jewish descent is a carrier of Canavan disease. The incidence of disease in this population is 1/3000 to 1/6000 [15-17].
Clinical features — Neonates with Canavan disease appear normal at birth, but after a few months, they fail to meet developmental milestones. Hypotonia with poor head control are early findings. After six months of age, head size increases and macrocephaly develops due to storage of NAA. Ultimately, affected children are unable to sit, walk, or talk and become spastic. Sleep disturbances, optic atrophy with blindness, feeding difficulties, and gastroesophageal reflux are also characteristic of the disease. Most children die within the first years of life, although survival to the second decade can be achieved. (See "Aspartoacylase deficiency (Canavan disease)".)
Testing — DNA sequencing for two pathogenic variants of the gene for Canavan disease can detect 98 percent of carriers in people of Ashkenazi Jewish descent. As with many of the genetic diseases seen in people of Ashkenazi Jewish descent , it is difficult to screen for Canavan disease in other populations due to its rarity and more diversity in pathogenic variants.
Several other techniques have been employed to detect affected fetuses or infants. An enzyme assay using cultured skin fibroblasts can be used to determine ASPA activity. This enzyme assay, however, cannot be performed on cultured amniocytes, chorionic villi cells, or blood due to normally low activity levels in these tissues, thus limiting its use in prenatal diagnosis.
By comparison, an analyte assay assessing levels of NAA can be performed on amniotic fluid or urine with the caveat that NAA levels in amniotic fluid are normally lower than those found in urine [18-21]. The American College of Medical Genetics and Genomics recommends that if known pathogenic variants cannot be identified for either parent, but both parents are suspected to be carriers based on biochemical analysis, amniocentesis should be offered between 16 and 18 weeks of gestation to measure the concentration of NAA in amniotic fluid and thus determine whether the fetus is affected [8].
Cystic fibrosis — Cystic fibrosis (CF) is a chronic, progressive pulmonary and exocrine pancreatic disease caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene.
Epidemiology — In people of Ashkenazi Jewish descent , the carrier frequency is 1/19 to 1/29 and the incidence of disease is 1/3300 [22,23].
Clinical features — CF typically involves the respiratory and gastrointestinal tracts and is characterized by chronic lung disease, recurrent pneumonia, pancreatic insufficiency, malabsorption, and diabetes mellitus. The clinical course is variable. In two-thirds of cases, the diagnosis is made in the first year of life. More severe disease tends to present at an earlier age than milder disease. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)
Testing — Hundreds of pathogenic variants in the gene for CFTR have been identified. The frequencies of pathogenic variants vary among different ethnic groups and geographic regions. In people of Ashkenazi Jewish descent , DNA sequencing for five pathogenic variants identifies 96 to 97 percent of the carriers [23]. Most laboratories screen for the 23 to 32 pathogenic variants that account for the vast majority of CF cases.
Since CF carrier detection rates and carrier frequencies are known across different ethnic and racial groups, screening for this disorder is also offered to couples who are not people of Ashkenazi Jewish descent. Complete analysis of the CFTR gene can be performed via DNA sequencing, but is not appropriate for routine carrier screening, as the results may be difficult to interpret. Carrier screening and indications for CFTR gene sequencing are reviewed in detail separately (see "Cystic fibrosis: Carrier screening"). All patients who have CFTR gene sequencing should have a consultation with a genetics professional.
Familial dysautonomia — Familial dysautonomia, also known as Riley-Day syndrome, is an autosomal recessive disease characterized by a progressive sensorimotor neuropathy, but sympathetic autonomic dysfunction is responsible for most clinical manifestations.
Epidemiology — Virtually all cases of familial dysautonomia have been reported in people of Ashkenazi Jewish descent. In this population, carrier frequency is 1/32, but may be as high as 1/18 in people of Polish Ashkenazi Jewish descent [24-27]. Disease incidence is 1/3700 in Israeli people of Ashkenazi Jewish descent [26].
Clinical features — Clinical manifestations are evident at birth and include feeding difficulties and hypotonia. Infants have significant gastroesophageal reflux, and, in turn, an increased risk of aspiration and chronic lung disease. Affected individuals have decreased pain and temperature perception. Autonomic dysfunction includes the absence of tears, severe episodes of nausea and vomiting, and rapid swings in blood pressure from severe hypertension to postural hypotension. Intelligence is usually normal. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)'.)
Testing — One major pathogenic variant accounts for 99.5 percent of pathogenic variants in people of Ashkenazi Jewish descent [28]. DNA sequencing is available for carrier testing. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)'.)
Fanconi anemia group C — Fanconi anemia is a genetic disorder characterized by several congenital anomalies (table 2), progressive bone marrow failure, and a higher prevalence of malignancies. The clinical manifestations are caused by disruption of normal DNA repair, which leads to genomic instability, abnormal cell cycle regulation, and cell death. Fanconi anemia may be caused by a pathogenic variant in one of many Fanconi anemia (FANC) genes. People of Ashkenazi Jewish descent have an especially high incidence of a pathogenic variant in FANCC known as IVS+4 A>T. Transmission is autosomal recessive. Mutations in the FANCC can also lead to uncontrolled cell growth due to lack of DNA repair processes and consequently an increased risk of blood or other cancers such as head and neck, skin, and gastrointestinal cancers. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics' and "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Clinical features'.)
Epidemiology — Carrier frequency of the FANCC pathogenic variant, also referred to as "Fanconi anemia group C," is approximately 1/66 to 1/128 in people of Ashkenazi Jewish descent compared with 1/156 to 1/209 in the general population [29]. Disease incidence in people of Ashkenazi Jewish descent is 1/32,000.
Clinical features — Fanconi anemia is associated with congenital anomalies affecting multiple organ systems with variable frequency. There is significant clinical variability in the disease, even within pedigrees. Affected individuals may have skin findings (hypo- or hyperpigmentation, cafe au lait spots); short stature; thumb or other radial ray abnormalities; microcephaly; and malformations of the eyes, ears, kidneys, or gonads. Cardiac, gastrointestinal, or neurologic abnormalities are occasionally seen. Neonates may have normal blood counts, but many patients develop cytopenias (especially thrombocytopenia) and eventually bone marrow failure. The risk of hematologic malignancies and solid tumors is increased. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Clinical features'.)
Treatment — Unlike several of the other genetic diseases in people of Ashkenazi Jewish descent , the bone marrow failure and hematologic malignancies associated with Fanconi anemia can be treated with hematopoietic cell transplantation (HCT). It is critical to test potential sibling donors for HCT to exclude those with Fanconi anemia.
Patients with Fanconi anemia require increased monitoring for organ dysfunction, bone marrow failure, and malignancies. If a patient with Fanconi anemia develops a malignancy that requires chemotherapy and/or radiation therapy, dose reductions or alternative regimens are likely to be necessary because of the increased sensitivity to DNA damage. Reduced intensity regimens are also used for HCT.
The survival of patients with Fanconi anemia has been dramatically improved with HCT; many individuals live well into adulthood. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Fanconi anemia'.)
Testing — The standard screening test for Fanconi anemia involves testing of lymphocytes for increased sensitivity to DNA damaging agents, followed by DNA sequencing in those with a positive result. However, in people of Ashkenazi Jewish descent , carrier screening can be done using DNA sequencing for the common FANCC IVS+4 A>T pathogenic variant. Some panels also test for a second pathogenic variant in FANCC, 322delG.
Familial hyperinsulinism — Familial hyperinsulinism, also known as ABCC8-related hyperinsulinism or persistent hyperinsulinemic hypoglycemia of infancy, is caused by pathogenic variants in the ABCC8 gene that lead to excessive pancreatic insulin secretion and, in turn, low blood glucose levels.
Epidemiology — Carrier frequency of familial hyperinsulinism in people of Ashkenazi Jewish descent is 1 in 68, with an incidence of disease of 1/18,000.
Clinical features — One-third of neonates with familial hyperinsulinism are macrosomic at delivery as a result of hyperinsulinemia during fetal life [30]. Within the first days of life, most infants have symptoms of hypoglycemia, such as poor feeding, lethargy, jitteriness, and hypotonia, although some may not be diagnosed until later in childhood. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)
Testing — Carrier testing is performed using molecular studies for pathogenic variants in the gene ABCC8.
Gaucher disease — Gaucher disease is a lysosomal disease caused by a deficiency of the enzyme glucocerebrosidase, which results in a reduced ability to degrade glucosylceramide. Consequently, glucosylceramide accumulates in macrophages of the reticuloendothelial system in the liver, spleen, bone marrow, and lungs.
Epidemiology — Gaucher disease is the most prevalent genetic disorder among people of Ashkenazi Jewish descent , and they account for two-thirds of all cases. The incidence of the disease in this population is 1/900. The carrier rate in people of Ashkenazi Jewish descent is 1/15, compared with 1/100 in the general population [23].
Clinical features — The disease is characterized by bone pain and fractures, thrombocytopenia, and hepatosplenomegaly. Onset of symptoms can occur at any time from infancy onward, but 50 percent of patients do not present until after 45 years of age. Neonatal onset of symptoms is not more common in people of Ashkenazi Jewish descent. Some cases are mild or asymptomatic [31,32]. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)
Testing — More than 100 pathogenic variants responsible for Gaucher disease have been identified, but seven account for more than 96 percent of pathogenic variants in people of Ashkenazi Jewish descent. DNA sequencing for these pathogenic variants can detect 97 percent of carriers [23,33-35]. Enzyme activity assays can help detect carriers who do not have one of these alleles [36]; in 80 percent of carriers for Gaucher disease, enzyme activity is 50 percent of normal. In the people who are not of Ashkenazi Jewish descent , only 74 percent of carriers can be detected with DNA sequencing alone. The addition of enzyme activity testing can increase testing sensitivity in this population [34].
If both parents carry a known pathogenic variant for Gaucher disease, prenatal diagnosis involving DNA sequencing of fetal cells obtained via amniocentesis or chorionic villus sampling should be offered. If both parents have been identified as carriers, but one or both do not carry a known pathogenic variant, prenatal diagnosis can be achieved by testing enzyme activity in cells from amniocentesis or chorionic villous samples or in amniotic fluid [37,38]. However, because of the wide variability in severity and age of onset, parents should be counseled that their child's ultimate phenotype cannot be accurately determined by prenatal testing.
Glycogen storage disease type I — Glycogen storage disease type I (GSDI) is associated with accumulation of glycogen in organs, including the liver, kidneys and small intestine, which leads to a variable degree of dysfunction of these organs [39].
Epidemiology — The incidence of GSDI in people of Ashkenazi Jewish descent is 1/16,000, with a carrier frequency of 1 in 64.
Clinical features — Symptoms related to GSDI usually manifest during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen. GSDI is associated with growth restriction, delayed puberty, lactic academia, and a high incidence of hepatic adenomas. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)
Testing — DNA sequencing detects 98 percent of carriers in people of Ashkenazi Jewish descent [40].
Joubert syndrome — Joubert syndrome is an autosomal recessive neurological disorder caused by abnormalities in the genes responsible for the structure and function of cilia, leading to abnormal development of the brainstem and cerebellar vermis.
Epidemiology — The incidence of Joubert syndrome in people of Ashkenazi Jewish descent is 1/34,000, with a carrier frequency of 1 in 102.
Clinical features — Joubert syndrome is characterized by cerebellar vermis hypoplasia resulting in ataxia, polydactyly, hypotonia, developmental delay, neonatal respiratory dysregulation, abnormal eye movements, and intellectual disability [41,42]. A pathognomonic finding on axial magnetic resonance imaging of the brain is the presence of prominent superior cerebellar peduncles, referred to as "molar tooth sign" of the midbrain-hindbrain junction.
NPHP or cystic renal dysplasia is seen in approximately one-fourth of cases [43]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome'.)
Testing — Carrier screening is performed by DNA sequencing for pathogenic variants in the TMEM216 gene.
Maple syrup urine disease — Maple syrup urine disease (MSUD) is an autosomal recessive disease caused by pathogenic variants in the BCKDHA, BCKDHB, and DBT genes, which encode proteins that are essential for breaking down the amino acids leucine, isoleucine, and valine. The urine of affected infants has a distinctive sweet odor.
Epidemiology — MSUD affects 1 in 185,000 live births. It occurs more frequently in certain populations such as Old Order Mennonite population with an incidence of up to 1 in 200. In people of Ashkenazi Jewish descent , it affects 1/50,000 live births with a carrier frequency of 1 in 81.
Clinical features — Classic MSUD is associated with ketonuria within 48 hours of birth, which leads to irritability, poor feeding, vomiting, lethargy, and dystonia. By four days of age, the infant can develop seizures, apnea, and signs of cerebral edema. Without treatment, this condition can be lethal. Affected individuals have developmental delays. (See "Overview of maple syrup urine disease".)
Testing — Carrier screening is performed to identify pathogenic variants involving BCKDHA, BCKDHB, and DBT genes. Individuals with MSUD are always homozygous or compound heterozygous for pathogenic variants in the gene [44,45]. Pathogenic variants in two different genes have not been associated with MSUD. Pathogenic variants in these genes account for >99 percent of MSUD in the population.
Mucolipidosis type IV — Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal disease. The disease is caused by accumulation of lipids and mucopolysaccharides in cell lysosomes due to abnormal endocytosis of normal membrane components. Unlike several of the other genetic diseases prevalent in people of Ashkenazi Jewish descent , no single aberrant protein has been identified as the cause of the disease. DNA sequencing has mapped the location of the pathogenic variant to a gene that encodes mucolipin 1, a membrane protein with unknown function [46].
Epidemiology — Over 100 cases of MLIV have been reported. Eighty percent of these cases have occurred in people of Ashkenazi Jewish descent. Carrier frequency is 1/100 and disease incidence is 1/40,000 among people of Ashkenazi Jewish descent [47].
Clinical features — MLIV is a progressive neurologic disorder characterized by physical and developmental delays, severe intellectual disability, corneal clouding, and retinal degeneration. Most affected individuals are diagnosed by age two to three years and never attain language skills or motor function beyond those of a one- to two-year-old. Patients with MLIV can have normal life spans, although life expectancy is poorly characterized due to the rarity of the disease.
Testing — Carrier screening is available for the pathogenic variants that account for more than 95 percent of individuals with the disorder in people of Ashkenazi Jewish descent [46,48]. A third pathogenic variant has also been identified but is not available for routine testing in most laboratories.
Niemann-Pick disease type A — Niemann-Pick disease type A (NPDA) is an autosomal recessive lysosomal disease. The disease is caused by a deficiency of acid sphingomyelinase, which results in accumulation of sphingomyelin in cell lysosomes.
Epidemiology — In people of Ashkenazi Jewish descent , carrier frequency is cited as 1/70 to 1/90 and disease incidence is cited as 1/25,600 to 1/32,000 [49,50].
Clinical features — Infants appear normal at birth. However, within the first few months of life, affected patients develop hepatosplenomegaly, feeding difficulties, and loss of early motor skills. Rapid, progressive, and profound loss of neurologic function leads to death by two to three years of age. A peripheral neuropathy manifested by hypotonia and absent reflexes, and macular cherry red spots on fundoscopic examination occur in approximately 50 percent of patients. There is no known treatment. (See "Overview of Niemann-Pick disease".)
Testing — Three pathogenic variants associated with NPDA are responsible for more than 95 percent of cases in people of Ashkenazi Jewish descent. Carrier screening with DNA sequencing is available for these pathogenic variants.
Tay-Sachs disease — Tay-Sachs disease is an autosomal recessive, neurodegenerative disease caused by excess storage of the cell membrane glycolipid, Gm2 ganglioside, within cell lysosomes. This Gm2 gangliosidosis is caused by a deficiency in beta-Hexosaminidase A (Hex A).
Epidemiology — In people of Ashkenazi Jewish descent , carrier frequency is 1/25 to 1/30 [23] and disease incidence is 1/3600, compared with 1/360,000 in other populations. Due to the founder effect, Tay-Sachs disease is also relatively more common in individuals of Pennsylvania Dutch, Southern Louisiana Cajun, or Eastern Quebec French Canadian descent. Because of screening protocols initiated in the 1970s targeting people of Ashkenazi Jewish descent , including premarital screening and prenatal testing, the number of cases of Tay-Sachs disease detected prenatally in the people not of Ashkenazi Jewish descent has increased three- to fourfold [51] and the disease burden from Tay-Sachs disease has been reduced by 90 percent in people of Ashkenazi Jewish descent [51].
Clinical features — The disease is characterized by normal motor development in the first few months of life. At two to six months of age, infants develop progressive weakness and loss of motor skills with hypotonia, hyperreflexia, and characteristic cherry red macula. Infants are commonly macrocephalic from accumulation of storage material in the brain. Ultimately, patients develop seizures, blindness, and spasticity. The life expectancy is two to five years, with death in most cases from pneumonia.
Testing — Testing for Tay-Sachs disease should be offered if either member of a couple is of Ashkenazi Jewish, French-Canadian, or Cajun descent or has a family history consistent with Tay-Sachs disease [5]. Testing identifies 99.9 percent of carriers in people of Ashkenazi Jewish descent , with a false-negative rate of less than 2 percent [23,52].
There are two forms of testing for the carrier state:
●DNA sequencing – In people of Ashkenazi Jewish descent, carrier testing with DNA sequencing is performed to detect the three pathogenic variants responsible for the vast majority of cases. In people who are not of Ashkenazi Jewish descent, DNA sequencing should also include testing for a fourth pathogenic variant, which accounts for 15 percent of pathogenic variants in this population.
●Enzyme analysis – Enzyme assays can measure activity of Hex A and Hex B in serum or leukocytes. Tay-Sachs disease carriers have decreased Hex A activity and normal or increased activity of Hex B. Enzyme analysis can also be performed on amniocytes or chorionic villus cells.
Although the enzyme test is cost-effective, it has several limitations. First, there may be overlap in carrier and noncarrier range, making the test inconclusive in some cases. The test also can be unreliable in pregnant patients and in women on hormonal forms of contraception. In these instances, serum levels of Hex A can be falsely elevated, increasing the likelihood of false-negative screening test results (a positive test is a low level of Hex A).
If biochemical screening is performed in pregnant people or people taking systemic hormonal contraceptives, leukocytes must be used. Biochemical testing also may identify carriers of pseudodeficiency alleles, which are alleles that are associated with decreased Hex A activity, but are not associated with the disease. For these reasons, ambiguous or positive biochemical results should be confirmed by DNA sequencing for the most common pathogenic variants.
Because of the limitations of biochemical testing discussed above, DNA sequencing should be performed first in people of Ashkenazi Jewish descent [52]. Biochemical analysis is recommended for people not of Ashkenazi Jewish descent or individuals with mixed ancestry (fewer than four grandparents of Ashkenazi Jewish descent) [8]. In a couple in which one partner carries a pathogenic variant causing Tay-Sachs disease, biochemical testing of the other partner may clarify whether they are a carrier with an unrecognized pathogenic variant. Gene sequencing can help identify rare pathogenic variants in individuals with a family history of Tay-Sachs disease, evaluate partners of known carriers of Tay-Sachs disease who have indeterminate enzyme analysis and negative common pathogenic variant analysis, and resolve ambiguous results from enzyme tests [53].
If both parents are carriers of known pathogenic variants, prenatal invasive testing via amniocentesis or chorionic villus sampling with DNA sequencing for the identified pathogenic variants should be offered. When both parents are known to be carriers, but one or both do not carry a known pathogenic variant, fetal cells obtained via amniocentesis or chorionic villus sampling should be tested for Hex A enzymatic activity [8]. Gene sequencing can help resolve ambiguous results from enzyme tests [53].
Usher syndrome — The most common forms of Usher syndrome in people of Ashkenazi Jewish descent are Type 1F and Type III.
Epidemiology — Type 1F Usher syndrome has an incidence of 1 in 86,000 and carrier frequency of 1 in 165, and type III has an incidence of 1 in 57,000 and carrier frequency of 1 in 107 in people of Ashkenazi Jewish descent.
Clinical features — Usher syndrome type 1F is associated with profound hearing loss that is present at birth. During childhood, affected individuals typically learn to walk at a later age than usual due to the associated vestibular areflexia. Signs of retinitis pigmentosa develop in childhood and visual fields become progressively constricted over time. (See "Retinitis pigmentosa: Clinical presentation and diagnosis".)
Usher syndrome type III is associated with the same features; however the hearing loss develops later in childhood and retinitis pigmentosa develops by the second decade of life.
Testing — Carrier testing is available by DNA sequencing.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal genetic screening and diagnosis".)
SUMMARY AND RECOMMENDATIONS
●Rationale for screening – At least one in five people of Ashkenazi Jewish descent is a carrier of a pathogenic variant for one of the diseases in a group of disorders sometimes termed "Jewish genetic disorders." For many of these genetic disorders, the pathogenic variant has only been identified in individuals of Ashkenazi Jewish descent. Most of these diseases are severe, untreatable, and associated with a shortened life expectancy. Carrier testing can often identify individuals at risk for offspring with one of these conditions. (See 'Introduction' above.)
●Panethnic approach – The author of this topic offers panethnic expanded carrier screening for disorders with a carrier frequency of ≥1/200 or a carrier frequency that is highly represented in one or more patient populations (such as Ashkenazi Jewish descendants), which is consistent with the ACMG approach. (See 'Panethnic approach' above.)
●Ethnic approach
•The ACOG Committee on Genetics recommends routinely offering all people of Ashkenazi Jewish ancestry carrier screening for four of the most common disorders that are either lethal or associated with significant morbidity: Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia, and considers offering an expanded panel an acceptable approach. The expanded panel would include these four disorders plus Bloom Syndrome, familial hyperinsulinism, Fanconi anemia group C, Gaucher disease, glycogen storage disease type I, Joubert syndrome, maple syrup urine disease, mucolipidosis IV, Niemann Pick disease type A, and Usher syndrome. (See 'Ethnic approach' above.)
•If an ethnic approach is used, the personal and family history of individuals considering pregnancy, or who are already pregnant, should be reviewed to determine whether either member of the couple is of Ashkenazi Jewish descent or has a relative with one or more genetic disorders (table 1). Ashkenazi Jewish ancestry is defined as any individual with one grandparent with known Ashkenazi Jewish ancestry, or those who have a relative with one of the genetic conditions prevalent in people of Ashkenazi Jewish descent. If an individual is unsure of their Ashkenazi Jewish ancestry, carrier screening is still offered. (See 'Ethnic approach' above.)
•For patients of Ashkenazi Jewish descent who do not have a family history of genetic disease, it is reasonable to screen for disorders with carrier detection rates ≥90 percent and population carrier frequency of ≥1 percent (table 1). (See 'Ethnic approach' above.)
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