American Journal of Medical Genetics 129A:162–164 (2004) Mutation Frequencies for Glycogen Storage Disease Ia in the Ashkenazi Jewish Population Josef Ekstein, 1 * Berish Y. Rubin, 2 Sylvia L. Anderson, 2 David A. Weinstein, 3 Gideon Bach, 4 Dvorah Abeliovich, 4 Michael Webb, 5 and Neil Risch 6,7 1 Dor Yeshorim, The Committee for the Prevention of Jewish Genetic Diseases, Brooklyn, New York 2 Department of Biological Sciences, Fordham University, Bronx, New York 3 Department of Medicine, Division of Endocrinology, Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 4 Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel 5 Tepnel Diagnostics Ltd., Abingdon Oxfordshire, England 6 Department of Genetics, Stanford University School of Medicine, Stanford, California 7 Division of Research, Kaiser Permanente, Oakland, California Glycogen storage disease type Ia (GSDIa) is a severe autosomal recessive disorder caused by deficiency of the enzyme D-glucose-6-phosphatase (G6Pase). While numerous mutations have been found in cosmopolitan European populations, Ashkenazi Jewish (AJ) patients appear to primar- ily carry the R83C mutation, but possibly also the Q347X mutation found generally in Caucasians. To determine the frequency for both these muta- tions in the AJ population, we tested 20,719 AJ subjects for the R83C mutation and 4,290 subjects for the Q347X mutation. We also evaluated the mutation status of 30 AJ GSDIa affected subjects. From the carrier screening, we found 290 subjects with R83C, for a carrier frequency for this muta- tion of 1.4%. This carrier frequency translates into a predicted disease prevalence of 1 in 20,000, five times higher than for the general Caucasian population, confirming a founder effect and ele- vated frequency of GSDIa in the AJ population. We observed no carriers of the Q347X mutation. Among the 30 GSDIa affected AJ subjects, all were homozygous for R83C. These results indicate that R83C is the only prevalent mutation for GSDIa in the Ashkenazi population. ß 2004 Wiley-Liss, Inc. KEY WORDS: glycogen storage disease type Ia; Ashkenazi Jews; glucose-6-phos- phatase INTRODUCTION Glycogen storage disease type Ia (von Gierke disease or GSDIa), is a recessive disease caused by deficiency of the enzyme D-glucose-6-phosphatase (G6Pase). This key enzyme catalyzes the synthesis of glucose from glucose-6-phosphate, and lack of activity results in severe hypoglycemia since both glycogenesis and gluconeogensis are impaired [Wolfsdorf and Weinstein, 2003]. The disease is rare in the general population (1 in 100,000), but is apparently increased in frequency in the Ashkenazi Jewish (AJ) population. The diagnosis of GSDIa was formerly dependent upon demonstration of impaired enzyme activity in liver biopsy specimens. With the identifica- tion of the gene for G6Pase [Lei et al., 1993], mutation analysis has become the preferred method for diagnosis. In addition, mutation analysis allows for carrier detection and prenatal diagnosis. To date, over 56 different mutations in the G6Pase gene from 300 unrelated patients have been reported [Rake et al., 2000]. Numerous studies document allelic heterogeneity in cosmopolitan European populations, with a few mutations occurring at an elevated frequency, namely R83C, 158delC, Q347X, R170X, and deltaF327 [Rake et al., 2000]. Such heterogeneity and the relatively high frequency of novel and/ or unique mutations create an impediment to general popula- tion screening. On the other hand, population isolates often have a more limited range of mutations. Such is the case in the AJ popu- lation, which has been shown repeatedly to have increased mutational homogeneity underlying Mendelian syndromes, such as the lysosomal storage diseases, familial dysautonomia, torsion dystonia, and Fanconi anemia. Indeed, such homo- geneity has also been demonstrated in the AJ population for GSDIa. In a study from Israel, all eight AJ GSDIa patients were homozygous for the R83C mutation [Parvari et al., 1997]. In a prior study in the United States, six of eight AJ patients were reported to be R83C homozygotes, with the remaining two reported to be compound heterozygotes for R83C and Q347X [Lei et al., 1995]. Thus, of a total of 32 GSDIa mutations in AJ patients, 30 (94%) were identified as R83C and 2 (6%) as Q347X. In this report, we describe our results of screening a large AJ population (from Dor Yeshorim, the Committee for the Prevention of Jewish Genetic Diseases) for the two mutations R83C and Q347X. We also report the results of mutation testing on 30 GSDIa patients with two AJ parents. MATERIALS AND METHODS The healthy subjects in this study were derived from the Dor Yeshorim Screening Program focusing on the orthodox AJ population. This study population has been described pre- viously [Broide et al., 1993; Abeliovich et al., 1996; Bach et al., 2001; Risch et al., 2003], and has been previously screened for a variety of recessive diseases prevalent in the AJ population. For analysis of the GSDIa R83C mutation, a total of 20,719 subjects were studied; for analysis of the Q347X mutation, *Correspondence to: Josef Ekstein, Dor Yeshorim, 429 Wythe Ave., Brooklyn, NY 11211. E-mail: jekstein@dor-yeshorim.com. Received 3 November 2003; Accepted 2 April 2004 DOI 10.1002/ajmg.a.30232 ß 2004 Wiley-Liss, Inc.