PRENATAL GENETIC SCREENING IN THE ASHKENAZI JEWISH POPULATION
Section snippets
The Prototype for Prenatal Genetic Screening: Tay-Sachs Disease
Tay-Sachs disease (GM2 gangliosidosis, type 1) has been the prototype for the prevention of genetic diseases by carrier screening, genetic counseling, and prenatal diagnosis for 30 years.31, 35 In 1969, Okada and O'Brien49 demonstrated that the deficiency of the lysosomal enzyme (β-hexosaminidase A) was the enzyme defect responsible for TSD. There are two major forms of this autosomal recessive disorder: (1) an infantile-onset neurodegenerative disease that is uniformly fatal in childhood and
Familial Dysautonomia
This disorder is an autosomal recessive neuropathy that almost exclusively affects infants of Ashkenazi Jewish descent.9 The carrier frequency is about 1 in 36. Familial dysautonomia is a disorder of sensory and autonomic function and is characterized by the absence of tearing, absence of fungiform papillae on the tongue, episodes of protracted vomiting, decreased discrimination to pain and temperature, and cardiovascular instability. The autonomic crises are life threatening; however, with
Type 1 Gaucher's Disease
This autosomal recessive lysosomal storage disease is one of the most prevalent disorders among Ashkenazi Jewish individuals with a carrier frequency of about 1 in 18.13 Type 1 Gaucher's disease results from the deficient activity of the lysosomal enzyme, acid β-glucosidase, and the resultant accumulation of the glycolipid, glucocerebrosidase, primarily in cells of the macrophage-monocyte system. Type 1 Gaucher's disease is clinically heterogeneous, ranging from early onset of severe disease
Prenatal Diagnosis
Prenatal diagnosis can be performed for each of the previous diseases by either chorionic villus sampling or amniocentesis.29 Although the measurement of β-hexosaminidase A in cultured cells remains the standard for prenatal diagnosis of TSD, in couples where parental mutations are known, DNA testing allows for an independent fetal diagnosis.64 In fact, the advent of molecular techniques in prenatal testing has allowed for the rapid expansion of genetic testing, particularly when functional
SUMMARY
The Ashkenazi Jewish community is a unique and ideal population in which to provide multiple disease screening because detection rates are high (>95%) by testing a limited number of mutations. The residual risk that remains is very low. In addition, the lessons learned from carrier screening in this community indicate that only through genetic counseling and education can screening in the general population gain wide acceptance and provide maximum benefit.
ACKNOWLEDGMENTS
This work was supported in part by grants from the National Institutes of Health, including a Merit Award (5 R37 DK34045), a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center, and a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center.
References (66)
- et al.
Familial dysautonomia is caused by mutations of the IKAP gene
Am J Hum Genet
(2001) - et al.
Cloning of the gene encoding a novel integral membrane protein, mucolipidin, and identification of the two major founder mutations causing mucolipidosis type IV
Am J Hum Genet
(2000) - et al.
Gaucher's disease: The origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations
Am J Hum Genet
(2000) - et al.
Enzyme therapy for Gaucher's disease: The first 5 years
Blood Rev
(1998) - et al.
Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population
Mol Genet Metab
(1998) - et al.
The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase
J Biol Chem
(1988) - et al.
Organization of the gene encoding the human beta-hexosaminidase alpha-chain
J Biol Chem
(1987) - et al.
Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia
Am J Hum Genet
(2001) - et al.
Detection of Tay-Sachs disease heterozygotes by assay of hexosaminidase A in serum and leukocytes
J Pediatr
(1971) Committee Opinion on Screening for Tay-Sachs Disease. ACOG Opinion 93
(1991)
Committee Opinion on Screening for Tay-Sachs Disease. ACOG Opinion 162
Mucolipidosis type IV: Clinical spectrum and natural history
Pediatrics
Identification of an altered splice site in Ashkenazi Tay-Sachs disease
Nature
Fanconi's anemia: Genetic testing in Ashkenazi Jews
Genet Test
Fanconi's anemia
Familial dysautonomia
Identification of the gene causing mucolipidosis type IV
Nat Genet
Aspartoacylase deficiency
Gaucher's disease
Genetic Diversity among Jews: Diseases and Markers at the DNA Level
Screening for carriers of Tay-Sachs disease in the ultraorthodox Ashkenazi Jewish community in Israel
Am J Med Genet
Molecular diagnosis and carrier screening for beta thalassemia
JAMA
A second mutation associated with apparent beta-hexosaminidase A pseudodeficiency: Identification and frequency estimation
Am J Hum Genet
Population-specific screening by mutation analysis for diseases frequent in Ashkenazi Jews
Hum Mutat
First-trimester biochemical and molecular diagnoses using chorionic villi: High accuracy in the U.S. collaborative study
Prenat Diagn
A fully automated method for identification of Tay-Sachs disease carriers by tear beta-hexosaminidase assay
Prog Clin Biol Res
Prenatal genetic carrier testing using triple disease screening
JAMA
Preimplantation genetic diagnosis principles and ethics
Hum Reprod
Bloom syndrome
Genetic Disorders Among the Jewish People
Cited by (12)
Carrier screening panels for Ashkenazi Jews: Is more better?
2005, Genetics in MedicineLysosomal storage disorders: The need for better pediatric recognition and comprehensive care
2004, Journal of PediatricsPrenatal healthcare providers Gaucher disease carrier screening practices
2012, Genetics in MedicineLysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals
2011, Genetics in MedicineCan population-based carrier screening be left to the community?
2009, Journal of Genetic Counseling
Address reprint requests to Robert J. Desnick, MD, PhD Department of Human Genetics Mount Sinai School of Medicine Fifth Avenue at 100th Street Box 1498 New York, NY 10029 e-mail: [email protected]