Ashkenazi Genetic Diseases – summaries

High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin.

Carrier screening for genetic disease in the Ashkenazi Jewish population

AU: Shahrabani-Gargir L, Shomrat R, Yaron Y, Orr-Urtreger A, Groden J, Legum C
SO: Genet Test. 1998;2(4):293.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by small stature, immunodeficiency, chromosomal instability, and a predisposition to different types of cancer. Although extremely rare in the general population, BS is seen in about 1 in 48,000 Ashkenazi Jews. Mutation analysis of seven Ashkenazi BS probands has shown that all were homozygous for the same mutation in the BLM gene: 2281delATCTGAinsTAGATTC, also known as blmAsh. This finding, along with the increased incidence of BS among Ashkenazi Jews, suggests a founder effect for BS in this population. The purpose of this study was to determine the frequency of blmAsh mutation carriers in a randomly sampled Ashkenazi Jewish population in Israel. The initial study group included 1,613 Ashkenazi Jews who were referred for routine DNA screening tests (cystic fibrosis, Gaucher, Canavan, fragile X). None had a family history of BS. A group of 552 non-Ashkenazi Jews served as controls. Mutation analysis was performed by PCR amplification followed by analysis of a specific BstN1 restriction site, created by the blmAsh mutation. All positive carriers were confirmed by direct sequencing. Sixteen blmAsh carriers were detected among 1,613 Ashkenazi Jews (1 in 101), compared to none among 552 non-Ashkenazi Jews. In this study, Ashkenazi Jews of biparental Polish descent had a significantly higher proportion of the blmAsh mutation (1 in 37) compared to Ashkenazi Jews of non-Polish descent. These results provide further evidence that a founder effect is responsible for the increased incidence of Bloom syndrome among Ashkenazi Jews, particularly those of Polish descent.

ADGenetic Institute, Sourasky Medical Center, Tel Aviv, Israel.
Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population/abstract/12?utdPopup=true

 


PATIENTS: Volunteer sample of 2824 Ashkenazi Jewish individuals enrolled as couples who were referred for TaySachs Disease testing.
INTERVENTION: Genetic counseling, education, and if chosen, genetic testing for any or all 3 disorders.
MAIN OUTCOME MEASURE: Acceptance of screening for each of the 3 disorders. Secondary outcomes include attitudes toward genetic testing and reproductive considerations.
RESULTS: Of the 2824 individuals tested for TSD, 97% and 95% also chose testing for CF and GD, respectively. The frequency of detected carriers was 1:21 for TSD, 1 :25 for CF, and 1:18 for GD. Twenty-one carriercoupleswere identified, counseled, and all postconception couples opted for prenatal diagnosis. Pre-education and posteducation questionnaires revealed that patients initially knew little about the diseases, but acquired disease information and increased knowledge of genetic concepts. Education and genetic counseling increased understanding and retention of genetic concepts and disease-related information, and minimized test-related anxiety. Although individuals sought screening for all 3 diseases, reproductive attitudes and decisions varied directly with disease severity and treatability.
CONCLUSIONS: These findings emphasize the importance of genetic counseling for prenatal carrier testing and may improve understanding, acceptance, and informed decision making for prenatal carrier screening for multiple genetic diseases.
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population/abstract/1?utdPopup=true


Carrier screening for genetic disease in the Ashkenazi Jewish population

Author:Ashley S Roman, MD, MPH
Section Editor:Louise Wilkins-Haug, MD, PhD
Deputy Editor:Vanessa A Barss, MD, FACOG

INTRODUCTION

When a mutant allele is introduced into a community that procreates mostly among themselves, the frequency of the allele will become higher in the community than in the general population. As a result, the community will have a higher incidence of rare genetic disorders associated with the allele, a situation known as the “founder effect.” The increased incidence of Tay-Sachs disease and several other disorders (table 1) among descendants of Ashkenazi Jews is an example of this phenomenon. Because these serious disorders are more common among Ashkenazi Jews, genetic carrier screening programs have been successful and have a high acceptance rate in this population.

APPROACH TO SCREENING

Rationale — Ashkenazi Jews are descendants of Jews from Central and Eastern Europe (eg, Germany, France, Poland, Hungary, Russia, Ukraine, Lithuania), while Sephardic Jews are descendants of Jews from Spain, Portugal, and North Africa. Individuals of Ashkenazi Jewish descent are an example of the founder effect. One in four to one in five individuals of Ashkenazi Jewish descent carry a mutation for one of the autosomal recessive disorders included in a group of disorders sometimes called “Jewish genetic disorders” [3]. Some of these disorders have a high incidence, primarily among individuals of Ashkenazi Jewish descent (eg, Tay-Sachs disease); for many of the disorders (eg, familial dysautonomia), the mutation has been identified almost exclusively in these individuals [1]. Some of the disorders (eg, cystic fibrosis) are also common in other high-risk ethnic groups. Although the disorders can also affect Sephardic Jews, non-Jews, and Jews from mixed backgrounds, they are less prevalent in these populations. Most of the disorders are severely disabling, untreatable, and associated with a shortened life expectancy.

Carrier screening in this population is performed to identify asymptomatic individuals who carry genetic mutations causing any of the genetic disorders more common in descendants of Ashkenazi Jews. If both parents are carriers of a mutation causing the same disorder, there is a one in four chance their offspring will inherit two copies of the mutation (one from each parent) and will be susceptible to developing the phenotype. Identification of these couples gives them the opportunity to 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.

Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population



Who is at risk of Tay-Sachs Disease?

Tay-Sachs carriers are found most frequently among families of eastern European Jewish descent (Ashkenazi Jews). In the United States today, approximately one in every 27 Jews is a Tay-Sachs carrier.

Screening is available for eleven genetic disorders. Carrier frequency is different for each condition — the overall chance of being a carrier for at least one of these diseases is 1 in 4 to 1 in 5 for someone of Ashkenazi Jewish descent.

http://www.tay-sachs.org/taysachs_disease.php



Ashkenazi Jewish Carrier Testing
The term Ashkenazi refers to individuals descended from the medieval Jewish communities of the Rhineland in the west of Germany. Many Ashkenazi Jews (AJ) migrated to other parts of Europe, with the majority migrating eastward.

The conditions for which carrier screening is offered are more common in individuals of Ashkenazi Jewish descent than other ethnic groups because of specific mutations that occurred in “founders” of the population. Because Jewish individuals historically married within their own ethnic group, these mutations increased in frequency over generations.

Screening is available for eleven genetic disorders. Carrier frequency is different for each condition — the overall chance of being a carrier for at least one of these diseases is 1 in 4 to 1 in 5 for someone of AJ descent.

https://www.ucsfhealth.org/education/ashkenazi_jewish_carrier_testing/



1 in 4 Ashkenazi Jews carries a genetic disorder that may threaten infant health.

Complete: Screens for 20 Jewish Genetic Diseases; meets ACOG and ACMG guidelines
Flexible: Blood, mouthwash or buccal swab specimens accepted†

Some genetic disorders are more prevalent in the Jewish population originating from Eastern and Central Europe. This group is known as Ashkenazi and it represents the vast majority of Jewish individuals in North America. Diseases that are more common among Ashkenazi Jews are referred to as Jewish Genetic Diseases. Most of these diseases are severe and associated with a shortened life expectancy.

One in four Ashkenazi Jews is a carrier of a genetic disorder that may threaten infant health. Patients who have at least one Ashkenazi Jewish grandparent are considered at risk.

Jewish Genetic Diseases are autosomal recessive disorders. When both parents are carriers of the same disorder, there is a 1 in 4, or 25%, chance with each pregnancy that they will have an affected child.

http://progenity.com/ajpnxt-jewish-carrier-screening


Below are the 19 Ashkenazic Jewish genetic diseases for which people are most commonly screened. It is estimated that 1 in 5 Ashkenazic Jews is a carrier of a mutation in at least one of these disease genes:

  1. Bloom Syndrome
  2. Canavan Disease
  3. Cystic Fibrosis
  4. Familial Dysautonomia
  5. Fanconi Anemia Type C
  6. Gaucher Disease
  7. Glycogen Storage Disease, Type 1a
  8. Maple Syrup Urine Disease
  9. Mucolipidosis IV (ML-IV)
  10. Niemann-Pick Disease Type A
  11. Tay-Sachs Disease
  12. Walker-Warburg Syndrome
  13. Dihyrolipoamide Dehydrogenase Deficiency (DLD Deficiency)
  14. Familial Hyperinsulinism
  15. Joubert Syndrome
  16. Nemaline Myopathy
  17. Spinal Muscular Atrophy
  18. Usher Syndrome Type 1F
  19. Usher Syndrome Type III

http://www.kveller.com/article/guide-to-jewish-genetic-diseases/

Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population


Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.
AUACOG Committee on Genetics
SOObstet Gynecol. 2009 Oct;114(4):950-3.

Certain autosomal recessive disease conditions are more prevalent in individuals of Eastern European Jewish (Ashkenazi) descent. Previously, the American College of Obstetricians and Gynecologists recommended that individuals of Eastern European Jewish ancestry be offered carrier screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis as part of routine obstetric care. Based on the criteria used to justify offering carrier screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, the American College of Obstetricians and Gynecologists’ Committee on Genetics recommends that couples of Ashkenazi Jewish ancestry also should be offered carrier screening for familial dysautonomia. Individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders. Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease.

Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population/abstract/4?utdPopup=true



Carrier screening for genetic disease in the Ashkenazi Jewish population

High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin.
AUShahrabani-Gargir L, Shomrat R, Yaron Y, Orr-Urtreger A, Groden J, Legum C
SOGenet Test. 1998;2(4):293.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by small stature, immunodeficiency, chromosomal instability, and a predisposition to different types of cancer. Although extremely rare in the general population, BS is seen in about 1 in 48,000 Ashkenazi Jews. Mutation analysis of seven Ashkenazi BS probands has shown that all were homozygous for the same mutation in the BLM gene: 2281delATCTGAinsTAGATTC, also known as blmAsh. This finding, along with the increased incidence of BS among Ashkenazi Jews, suggests a founder effect for BS in this population. The purpose of this study was to determine the frequency of blmAsh mutation carriers in a randomly sampled Ashkenazi Jewish population in Israel. The initial study group included 1,613 Ashkenazi Jews who were referred for routine DNA screening tests (cystic fibrosis, Gaucher, Canavan, fragile X). None had a family history of BS. A group of 552 non-Ashkenazi Jews served as controls. Mutation analysis was performed by PCR amplification followed by analysis of a specific BstN1 restriction site, created by the blmAsh mutation. All positive carriers were confirmed by direct sequencing. Sixteen blmAsh carriers were detected among 1,613 Ashkenazi Jews (1 in 101), compared to none among 552 non-Ashkenazi individuals. In this study, Ashkenazi Jews of biparental Polish descent had a significantly higher proportion of the blmAsh mutation (1 in 37) compared to Ashkenazi Jews of non-Polish descent. These results provide further evidence that a founder effect is responsible for the increased incidence of Bloom syndrome among Ashkenazi Jews, particularly those of Polish descent.
ADGenetic Institute, Sourasky Medical Center, Tel Aviv, Israel.

Source:

Jewish Genetic Diseases
Overview, FAQs and Resources
What are Jewish Genetic Diseases?
Jewish genetic diseases are a group of disorders that occur with higher frequency in the Jewish
population. The Ashkenazi Jews, those whose ancestors were from Central and Eastern Europe
(i.e. Poland, Russia, Germany, Lithuania, etc.) are at higher risk than the general population for
several genetic diseases. This is primarily due to the fact that the Jewish communities in Europe
were small and isolated, and members tended to marry within those communities. Since it is
estimated that all individuals carry a small number of gene changes (called mutations), the ones
present in those small groups of European Jews became more prevalent in future generations.
What are the diseases that are more prevalent in the Ashkenazi Jewish population?
Face the Facts, it’s not just Tay-Sachs! Currently, there is carrier testing for 18 preventable
genetic diseases affecting Ashkenazi Jews, most of which are life threatening. Below are brief
descriptions of each disorder with the approximate carrier rate (the proportion of Ashkenazi Jews
who have a single copy of the specific recessive gene mutation) in parenthesis. Below are the
Ashkenazi Jewish genetic diseases most commonly screened for:
1. Bloom Syndrome – Characterized by short stature, a sun-sensitive skin rash, an increased
susceptibility to infections and higher incidence of leukemia and other cancers. (1 in 100)
2. Canavan Disease – A neurodegenerative disorder that presents with normal development
until 2-4 months and then there is a progressive loss of skills. Those affected typically die
in childhood but may live into adolescence. (1 in 40)
3. Cystic Fibrosis – Causes the body to produce thick mucus that accumulates in the lungs
and digestive tract, resulting in lung infections and poor growth. (1 in 25)
4. Familial Dysautonomia – Causes the autonomic and sensory nervous system to
malfunction, affecting the regulation of body temperature, blood pressure and stress
response, and causes decreased sensitivity to pain. Frequent pneumonia and poor growth
may occur. (1 in 30)
5. Fanconi Anemia Type C – Associated with short stature, bone marrow failure, and a
predisposition to leukemia and other cancers. Some children have limb, heart or kidney
abnormalities and learning difficulties. (1 in 89)
6. Gaucher Disease Type 1 – A variable condition both in age of onset and symptoms. It
may present with a painful, enlarged spleen, anemia, and low white blood cell count.
Bone deterioration is a major cause of pain and disability. Treatment is available. (1 in
14)
7. Glycogen Storage Disease, Type 1a – A metabolic disorder that causes poor blood sugar
maintenance with sudden drops in blood sugar, growth failure, enlarged liver and anemia.
Disease management involves lifelong diet modification. (1 in 71)
8. Maple Syrup Urine Disease – A variable disorder of amino acid metabolism. Named for
the characteristic maple syrup smell of urine in those with the disorder. With careful
dietary control, normal growth and development is possible. If untreated, it can lead to
poor feeding, lethargy, seizures and coma. (1 in 81)
9. Mucolipidosis IV (ML4) – A progressive neurological disorder with variable symptoms
beginning in infancy. Characteristics include muscle weakness, severe intellectual
disabilities and eye problems. (1 in 125)
10. Niemann-Pick Disease Type A – A progressive neurodegenerative disease in which a
harmful amount of fatty substance accumulates in different parts of the body leading to
death by age two to four years old. (1 in 90)
11. Tay-Sachs Disease – An apparently healthy child begins to lose skills around 4-6 months
of age and there is a progressive neurological decline leading to blindness, seizures and
unresponsiveness. Death usually occurs by the age of 4-6. (1 in 25)
12. Dihydrolipoamide Dehydrogenase Deficiency (DLD Deficiency) – Presents in early
infancy with poor feeding, frequent episodes of vomiting, lethargy and developmental
delay. Affected individuals develop seizures, enlarged liver, blindness and ultimately
suffer an early death. (1 in 96)
13. Familial Hyperinsulinism – Characterized by hypoglycemia that can vary from mild to
severe. It can be present in the immediate newborn period through the first year of life
with symptoms such as seizures, poor muscle tone, poor feeding and sleep disorders.
Medical or surgical management can control glucose levels. (1 in 66)
14. Joubert Syndrome – Characterized by structural malformations of the cerebellar vermis.
The most common features of Joubert syndrome in infants include abnormally rapid
breathing, hypotonia, jerky eye movements (oculomotor apraxia), developmental delay,
and ataxia. Kidney and liver abnormalities can develop, and seizures may also occur. (1
in 92)
15. Nemaline Myopathy – This is the most common congenital myopathy. Infants are born
with hypotonia and usually have problems with breathing and feeding. Later, some
skeletal problems may arise, such as scoliosis (curvature of the spine). In general, the
weakness does not worsen during life but development is delayed. (1 in 66)
16. Spinal Muscular Atrophy (SMA) – A group of diseases affecting the motor neurons of
the spinal cord and brain stem, which are responsible for supplying electrical and
chemical signals to muscle cells. Without proper signals, muscle cells do not function
properly and become much smaller (atrophy), leading to muscle weakness. Individuals
affected with SMA have progressive muscle degeneration and weakness, eventually
leading to death. (1 in 41)
17. Usher Syndrome Type 1F – Characterized by profound hearing loss which is present at
birth, and adolescent-onset retinitis pigmentosa, a disorder that significantly impairs
vision. (1 in 141)
18. Usher Syndrome Type III – Causes progressive hearing loss and vision loss. Hearing is
often normal at birth with progressive hearing loss typically beginning during childhood
or early adolescence. Often leads to blindness by adulthood. (1 in 107)



Medline ® Abstract for Reference 13
of ‘Carrier screening for genetic disease in the Ashkenazi Jewish population’

13
PubMed
TICarrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population.
AULi L, Eng C, Desnick RJ, German J, Ellis NA
SOMol Genet Metab. 1998;64(4):286.

Bloom syndrome is more common in individuals of Ashkenazi Jewish descent than in any other population, and one particular mutation in the Bloom syndrome gene, blmAsh, is homozygous in nearly all Ashkenazi Jewish persons with Bloom syndrome. We have determined the frequency of blmAsh in 1491 Ashkenazi Jewish persons with no known history of Bloom syndrome and found that 1 in 107 persons was heterozygous. Although not common, genetic screening for Bloom syndrome is feasible in this population.
ADDepartment of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, New York 10029, USA.

http://www.uptodate.com/contents/bloom-syndrome/abstract/3-6



Medline ® Abstract for Reference 13
of ‘Carrier screening for genetic disease in the Ashkenazi Jewish population’

13
PubMed
TICarrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population.
AULi L, Eng C, Desnick RJ, German J, Ellis NA
SOMol Genet Metab. 1998;64(4):286.

Bloom syndrome is more common in individuals of Ashkenazi Jewish descent than in any other population, and one particular mutation in the Bloom syndrome gene, blmAsh, is homozygous in nearly all Ashkenazi Jewish persons with Bloom syndrome. We have determined the frequency of blmAsh in 1491 Ashkenazi Jewish persons with no known history of Bloom syndrome and found that 1 in 107 persons was heterozygous. Although not common, genetic screening for Bloom syndrome is feasible in this population.
ADDepartment of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, New York 10029, USA.



UpToDateWolters Kluwer Health
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Medline ® Abstract for Reference 18
of ‘Carrier screening for genetic disease in the Ashkenazi Jewish population’

18
PubMed
TISpongy degeneration of the brain, Canavan disease: biochemical and molecular findings.
AUMatalon RM, Michals-Matalon K
SOFront Biosci. 2000;5:D307.

Canavan disease is a severe progressive leukodystrophy characterized by swelling and spongy degeneration of the white matter of the brain. It is an autosomal recessive disease found more frequently among Ashkenazi Jews. The clinical features are those of severe mental retardation with inability to gain developmental milestones. Hypotonia, head lag and macrocephaly are characteristic of Canavan disease and become apparent after 5-6 months of age. Massive excretion in the urine of N-acetylaspartic acid is the biochemical marker for Canavan disease, which is caused by deficiency of the enzyme aspartoacylase. This discovery allowed for accurate diagnosis of Canavan disease, while prior to that, a brain biopsy was needed. The gene for aspartoacylase has been cloned and two mutations predominate among Ashkenazi Jewish individuals with Canavan disease and account for more than 98% of the Ashkenazi Jewish patients. The mutations among other ethnic groups are more diverse. The carrier frequency for the two common mutations among Ashkenazi Jews was found to be surprisingly high, 1:37. Screening for carriers is now common practice for this population. A knock-out mouse for Canavan disease is being genetically engineered in our laboratory. The mouse model will allow for development of strategies for gene therapy.
ADDepartment of Pediatrics, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-0359, USA. rmatalon@utmb.edu
PMID10704428



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Medline ® Abstract for Reference 28
of ‘Carrier screening for genetic disease in the Ashkenazi Jewish population’
Screening for familial dysautonomia in Israel: evidence for higher carrier rate among Polish Ashkenazi Jews.
AULehavi O, Aizenstein O, Bercovich D, Pavzner D, Shomrat R, Orr-Urtreger A, Yaron Y
SOGenet Test. 2003;7(2):139.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by hereditary sensory and autonomic neuropathies. Although extremely rare in most populations, FD is common among Ashkenazi Jews (AJ), with a calculated carrier frequency of 1 in 30, based on disease prevalence. The gene for FD was recently identified as IKBKAP. One major mutation (IVS2 + 6T –>C) is responsible in>99.5% of cases among AJ. The purpose of this study was to determine the actual frequency of FD carriers in the AJ population in Israel and to determine whether carriers are more frequent among a subpopulation of AJ from Poland. The study group included 1267 Jews of Ashkenazi origin who were referred for routine DNA screening tests. These included 1100 individuals who were full AJ and 167 who were part AJ. None had a family history of FD. Mutation analysis for (IVS2 + 6T –>C) was performed by PCR amplification followed by restriction enzyme analysis. All positive cases were confirmed by DHPLC WAVE( trade mark ). Among the 1100 full AJ tested, 34 were found to be FD carriers (1:32). The incidence of mutation carriers was significantly higher in AJ of Polish descent (1:18) compared to AJ of non-Polish descent (1:99). Among the 167 individuals who were part AJ, there were 3 carriers (1:56). The incidence of FD among AJ, particularly those of Polish background, warrants population screening. Population screening may be performed by denaturing high-performance liquid chromatography.

ADPrenatal Diagnosis Division, Genetic Institute and Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv, Israel.
PMID12885336



Medline ® Abstract for Reference 29
of ‘Carrier screening for genetic disease in the Ashkenazi Jewish population’

Incidence of familial dysautonomia in Israel 1977-1981.
AUMaayan C, Kaplan E, Shachar S, Peleg O, Godfrey S
SOClin Genet. 1987;32(2):106.

The incidence of all diagnosed cases of familial dysautonomia in Israel among Ashkenazi Jews from 1977-1981 was 27/100,000 or 1/3703. This incidence is higher than that previously reported in Israel in 1967 or 8.3/100,000 (1/12,048) (Moses et al. 1967). It is also higher than that of North American Ashkenazi Jews in 1970, when the rate was 5-10/100,000 (1/10,000-20,000) (Brunt&McKusick 1970). This higher incidence could be explained by current awareness of the diagnosis, or by the emergence of more cases.
ADDepartment of Pediatrics, Hadassah University Hospital, Mount Scopus, Israel.



UpToDateWolters Kluwer Health

Carrier screening for genetic disease in the Ashkenazi Jewish population’32
PubMed
TICarrier frequency of the IVS4 + 4 A–>T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population.
AUVerlander PC, Kaporis A, Liu Q, Zhang Q, Seligsohn U, Auerbach AD
SOBlood. 1995;86(11):4034.

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous autosomal recessive disorder defined by a cellular hypersensitivity to DNA cross-linking agents. One of the FA genes, FAC, has been cloned and the genomic structure of the coding region has been characterized. We have developed amplification refractory mutation system (ARMS) assays for five known mutations in FAC, and have applied these assays to determine the carrier frequency of the IVS4 + 4 A–>T (IVS4) mutation in an Ashkenazi Jewish population. We tested 3,104 Jewish individuals, primarily of Ashkenazi descent, for the two most common FAC mutations, IVS4 and 322delG. Thirty-five IVS4 carriers were identified, for a carrier frequency of 1 in 89 (1.1%; 95% confidence interval 0.79% to 1.56%); no 322delG carriers were found. To determine if the IVS4 mutation was confined to the Ashkenazi Jewish population, we tested 563 Iraqi Jews for IVS4, and no carriers were found. Because the IVS4 mutation has only been found on chromosomes of Ashkenazi Jewish origin and is the only FAC mutation found on these chromosomes, we suggest that a founder effect is responsible for the high frequency of this mutation. With a carrier frequency greater than 1% and simple testing available, the IVS4 mutation merits inclusion in the battery of tests routinely provided to the Jewish population.
ADLaboratory of Human Genetics and Hematology, Rockefeller University, New York, NY 10021-6399, USA.
PMID7492758
Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population/abstract/32?utdPopup=true



Carrier screening for genetic disease in the Ashkenazi Jewish population

current BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.
AUNeuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, Hampel H, Borgen P, Brown K, Skolnick M, Shattuck-Eidens D, Jhanwar S, Goldgar D, Offit K
SONat Genet. 1996;13(1):126.

The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.
ADDepartment of Human Genetics, Sloan-Kettering Cancer Center, New York, New York 10021, USA.
PMID8673092

Source: http://www.uptodate.com/contents/carrier-screening-for-genetic-disease-in-the-ashkenazi-jewish-population/abstract/41?utdPopup=true



Ashkenazi Jewish population frequency of the Bloom syndrome gene 2281 delta 6ins7 mutation.
Roa BB1, Savino CV, Richards CS.
Author information
1Baylor DNA Diagnostic Laboratory, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract
Bloom syndrome is an autosomal recessive disorder characterized clinically by small size, sun-sensitive facial erythema, and immunodeficiency, and cytogenetically by increased chromosome breakage and sister chromatid exchange. Genomic instability renders Bloom syndrome patients at elevated risk for multiple cancers. Bloom syndrome occurs most commonly in the Ashkenazi Jewish population due to an apparent founder effect. The BLM gene on chromosome 15q26.1 was identified to encode a RecQ DNA helicase. Multiple mutations were identified, with Ashkenazi Jewish Bloom syndrome patients almost exclusively homozygous for a complex frameshift mutation (6-bp deletion/7-bp insertion at BLM nucleotide 2,281). This molecular genetic study seeks to verify the Ashkenazi Jewish carrier frequency of the BLM 2281 delta 6ins7 allele using semiautomated allele-specific oligonucleotide (ASO) analysis. Anonymized DNA samples from 1,016 Ashkenazi Jewish individuals and 307 non-Jewish individuals were screened. Ten Ashkenazi heterozygote carriers for the 2281 delta 6ins7 mutation were identified, giving a carrier frequency estimate of 0.98%, or approximately 1 carrier out of 102 individuals in the Ashkenazi Jewish population. These results are consistent with previous estimates, and combining our findings with the published molecular data collectively yields an Ashkenazi Jewish carrier frequency of approximately 1 in 104. Given its high population frequency and detection rate among Ashkenazi Jewish patients, the blmAsh mutation constitutes an appropriate addition to screening panels for Ashkenazi Jewish disease testing.
http://www.ncbi.nlm.nih.gov/pubmed?term=10464671



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Ashkenazi Genetic Diseases – summaries