Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases

The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease‐causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ‐descended individuals, screening for 16 disorders resulted in ∼1 in 3.3 being a carrier for one disease and ∼1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ∼15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease‐causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population. Hum Mutat 31:1–11, 2010. © 2010 Wiley‐Liss, Inc.

[1]  R. Carmi,et al.  Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population , 1998, Human mutation.

[2]  C. Petit.  Usher syndrome: from genetics to pathogenesis. , 2001, Annual review of genomics and human genetics.

[3]  L. Edelmann,et al.  Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. , 2001, American journal of human genetics.

[4]  Karen B Avraham,et al.  A mutation of PCDH15 among Ashkenazi Jews with the type 1 Usher syndrome. , 2003, The New England journal of medicine.

[5]  ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. , 2009, Obstetrics and Gynecology.

[6]  ACOG committee opinion. Number 298, August 2004. Prenatal and preconceptional carrier screening for genetic diseases in individuals of Eastern European Jewish descent. , 2004, Obstetrics and gynecology.

[7]  R. Desnick,et al.  Premarital and prenatal screening for cystic fibrosis: Experience in the Ashkenazi Jewish population , 2004, Genetics in Medicine.

[8]  D. Chitayat,et al.  Canavan disease: Carrier‐frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay , 2004, American journal of medical genetics. Part A.

[9]  B. Rubin,et al.  Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene , 2004, Human Genetics.

[10]  H. Katzenstein,et al.  The Dor Yeshorim story: community-based carrier screening for Tay-Sachs disease. , 2001, Advances in genetics.

[11]  S. Korman,et al.  Identification of a common mutation (Gly194Cys) in both Arab Moslem and Ashkenazi Jewish patients with dihydrolipoamide dehydrogenase (E3) deficiency: Possible beneficial effect of vitamin therapy , 2003, Journal of Inherited Metabolic Disease.

[12]  R. Desnick,et al.  Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews. , 2002, American journal of medical genetics.

[13]  Arlene Buller,et al.  Technical validation of a multiplex platform to detect thirty mutations in eight genetic diseases prevalent in individuals of Ashkenazi Jewish descent , 2005, Genetics in Medicine.

[14]  R. Desnick,et al.  Genetic homogeneity and phenotypic variability among Ashkenazi Jews with Usher syndrome type III , 2003, Journal of medical genetics.

[15]  C. Eng,et al.  Experiences in molecular-based prenatal screening for Ashkenazi Jewish genetic diseases. , 2001, Advances in genetics.

[16]  Weimin Sun,et al.  Technical validation of a TM Biosciences Luminex-based multiplex assay for detecting the American College of Medical Genetics recommended cystic fibrosis mutation panel. , 2006, The Journal of molecular diagnostics : JMD.

[17]  T. Owaidah,et al.  Knowledge and Attitude Toward the Hemoglobinopathies Premarital Screening Program in Saudi Arabia: Population-Based Survey , 2008, Hemoglobin.

[18]  R. Desnick,et al.  Type 1 Gaucher disease: significant disease manifestations in "asymptomatic" homozygotes. , 2010, Archives of internal medicine.

[19]  Maria Cristina Rosatelli,et al.  Screening for thalassemia: a model of success. , 2002, Obstetrics and gynecology clinics of North America.

[20]  C. Richards,et al.  Population‐specific screening by mutation analysis for diseases frequent in Ashkenazi Jews , 1996, Human Mutation.

[21]  H. Mandel,et al.  Population screening in a Druze community: the challenge and the reward , 2008, Genetics in Medicine.

[22]  W. Greenhalf,et al.  Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers , 2005, Human mutation.

[23]  E. Friedman,et al.  Bloom syndrome and Fanconi's anemia: rate and ethnic origin of mutation carriers in Israel. , 2002, The Israel Medical Association journal : IMAJ.

[24]  N. Risch,et al.  Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population , 2004, American journal of medical genetics. Part A.

[25]  M. Balwani,et al.  Biochemical and molecular diagnosis of lipoamide dehydrogenase deficiency in a North American Ashkenazi Jewish family , 2006, Journal of Inherited Metabolic Disease.

[26]  G. Palomaki,et al.  Technical standards and guidelines for reproductive screening in the Ashkenazi Jewish population , 2008, Genetics in Medicine.

[27]  Y. Anikster,et al.  The frequency of the C854 mutation in the aspartoacylase gene in Ashkenazi Jews in Israel. , 1994, American journal of human genetics.

[28]  Weimin Sun,et al.  Molecular screening for diseases frequent in Ashkenazi Jews: Lessons learned from more than 100,000 tests performed in a commercial laboratory , 2004, Genetics in Medicine.

[29]  M. Hildesheimer,et al.  The R245X Mutation of PCDH15 in Ashkenazi Jewish Children Diagnosed with Nonsyndromic Hearing Loss Foreshadows Retinitis Pigmentosa , 2004, Pediatric Research.

[30]  D. Lancet,et al.  Mucolipidosis type IV: Novel MCOLN1 mutations in Jewish and non‐Jewish patients and the frequency of the disease in the Ashkenazi Jewish population , 2001, Human mutation.

[31]  B. Pletcher,et al.  Carrier screening in individuals of Ashkenazi Jewish descent , 2008, Genetics in Medicine.

[32]  K. Klinger,et al.  Laboratory standards and guidelines for population-based cystic fibrosis carrier screening , 2001, Genetics in Medicine.

[33]  L. Feuk,et al.  Detection of large-scale variation in the human genome , 2004, Nature Genetics.

[34]  D. Bercovich,et al.  Screening for familial dysautonomia in Israel: evidence for higher carrier rate among Polish Ashkenazi Jews. , 2003, Genetic testing.

[35]  Yuhua Song,et al.  Cystic fibrosis carrier screening: Validation of a novel method using BeadChip technology , 2004, Genetics in Medicine.

[36]  Michael M. Kaback,et al.  Population-based genetic screening for reproductive counseling: the Tay-Sachs disease model , 2000, European Journal of Pediatrics.

[37]  A. Auerbach,et al.  Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. , 1995, Blood.

[38]  G. Patrinos,et al.  Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies , 2005, Human mutation.

[39]  C. Eng,et al.  Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population. , 1998, Molecular genetics and metabolism.

[40]  K. Voelkerding,et al.  Next-generation sequencing: from basic research to diagnostics. , 2009, Clinical chemistry.

[41]  E. Schuchman,et al.  Niemann-Pick disease: mutation update, genotype/phenotype correlations, and prospects for genetic testing. , 1997, Genetic testing.

[42]  F. Fares,et al.  Carrier frequency of autosomal‐recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? , 2008, Prenatal diagnosis.

[43]  I. Lerer,et al.  Cystic Fibrosis Heterozygote Screening in the Orthodox Community of Ashkenazi Jews: The Dor Yesharim Approach and Heterozygote Frequency , 1996, European journal of human genetics : EJHG.

[44]  J. Groden,et al.  High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin. , 1998, Genetic testing.

[45]  C. Eng,et al.  Prenatal genetic carrier testing using triple disease screening. , 1997, JAMA.

[46]  W. Grody,et al.  Keeping up with the next generation: massively parallel sequencing in clinical diagnostics. , 2008, The Journal of molecular diagnostics : JMD.

[47]  S. Poths,et al.  Array-Based Resequencing Assay for Mutations Causing Hypertrophic Cardiomyopathy , 2008, Clinical chemistry.

[48]  B. Lerner.  When diseases disappear--the case of familial dysautonomia. , 2009, The New England journal of medicine.

[49]  I. Schrijver,et al.  Comprehensive arrayed primer extension array for the detection of 59 sequence variants in 15 conditions prevalent among the (Ashkenazi) Jewish population. , 2007, The Journal of molecular diagnostics : JMD.

[50]  H. Mandel,et al.  Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews. , 1999, American journal of medical genetics.

[51]  Victoria M. Pratt,et al.  Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel , 2004, Genetics in Medicine.

[52]  M. Permutt,et al.  Mutations in the sulonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. , 1996, Human molecular genetics.

[53]  M. Kaback,et al.  Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. , 1993, JAMA.

[54]  J. Warrington,et al.  Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray , 2008, Genetics in Medicine.

[55]  R. Desnick,et al.  Carrier screening for mucolipidosis type IV in the American Ashkenazi Jewish population. , 2002, American journal of human genetics.

[56]  L. Edelmann,et al.  Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent. , 2009, The Journal of molecular diagnostics : JMD.

[57]  J. Ekstein,et al.  The frequency of mucolipidosis type IV in the Ashkenazi Jewish population and the identification of 3 novel MCOLN1 mutations , 2005, Human mutation.

[58]  M. Zeigler,et al.  Screening for carriers of Tay-Sachs disease in the ultraorthodox Ashkenazi Jewish community in Israel. , 1993, American journal of medical genetics.