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,2Sylvia L. Anderson,2David A. Weinstein,3Gideon Bach,4
Dvorah Abeliovich,4Michael Webb,5and Neil Risch6,7
1Dor Yeshorim, The Committee for the Prevention of Jewish Genetic Diseases, Brooklyn, New York
2Department of Biological Sciences, Fordham University, Bronx, New York
3Department of Medicine, Division of Endocrinology, Children’s Hospital and Department of Pediatrics,
Harvard Medical School, Boston, Massachusetts
4Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel
5Tepnel Diagnostics Ltd., Abingdon Oxfordshire, England
6Department of Genetics, Stanford University School of Medicine, Stanford, California
7Division 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-
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 30GSDIa affectedAJ subjects, allwere
homozygous for R83C. These results indicate that
R83C is the only prevalent mutation for GSDIa in
the Ashkenazi population.
? 2004 Wiley-Liss, Inc.
KEY WORDS:glycogen storage disease type Ia;
Ashkenazi Jews; glucose-6-phos-
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 diseaseis rare inthegeneral 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-
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
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-
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,
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 etal., 1997].
In a prior study in the United States, six of eight AJ patients
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
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
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.,
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: firstname.lastname@example.org.
Received 3 November 2003; Accepted 2 April 2004
? 2004 Wiley-Liss, Inc.
4,290 subjects were examined. The subjects included in this
study were anonymous and the researchers had no knowledge
of any relationship among them. All were unselected as far as
family history for GSDIa is concerned, with the only require-
ment being AJ ancestry. Therefore, the sample is a random
the carrier frequencies we estimated are unbiased. It is
possible that some subjects were related, for example, as sibs
or cousins, but given the restricted age range we expect the
number to be small. In any event, such relatedness would not
affect the estimated allele frequencies but rather the standard
errors for these frequencies [Risch et al., 2003].
Genotyping of mutations was performed by three labora-
tories, Orchid BioSciences, Abingdon, England, Fordham
University, Bronx, NY, and Hadassah Hospital, Jerusalem,
Israel. Orchid uses allele specific amplification technology as
(ARMSTM) [Newton et al., 1989]; the laboratory at Fordham
uses SSCP analysis of PCR products; and the laboratory at
Hadassah uses restriction analysis following PCR.
To estimate carrier frequencies, we divided the number of
detected carriers by the number of tested subjects. To obtain
allele frequencies, we simply divided the carrier frequency by
two (a close approximation when the carrier frequency is
Thirty subjects affected with GSDIa with two AJ parents
were genotyped at Children’s Hospital, Boston. The mutations
for none of these subjects have been reported in the literature
previously. Complete sequencing of all five exons of the
glucose-6-phosphatase gene was performed using the protocol
described by Lei et al. . Mutations were confirmed in
duplicate in both the forward and reverse directions.
These studies were approved by institutional review boards
at the respective institutions, and informed consent was
obtained for all adult subjects and parental consent for any
minors where applicable.
and Q347X are given in Table I. We found 290 carriers of the
R83C mutation out of 20,719 subjects tested, for a carrier rate
of 0.014. We found no carriers of the Q347X mutation out of
of less than 1/4,290¼0.00023 in the Ashkenazi population. Of
the 30 AJ affected subjects tested, all were homozygous for the
However, one study found two of eight AJ subjects that were
compound heterozygotes forR83C andQ347X, thelatter being
the most common mutation in Caucasians of Western Eur-
opean heritage. A primary concern in this study was to
determine the frequency of the Q347X mutation along with
the R83C mutation in the AJ population. The fact that we did
not detect a single carrier of the Q347X mutation out of over
4,000 subjects tested suggests that the R83C mutation is the
only GSDIa mutation prevalent in this group. This conclusion
only one found among 30 affected AJ subjects.
When two prior studies are combined [Lei et al., 1995;
Parvari et al., 1997], out of a total of 32 mutations observed in
affected AJ subjects, 30 were found to be R83C and 2 were
of over 20,000 AJ subjects, we observed a carrier frequency of
the R83C mutation of 1.4%. On this basis, assuming a
frequency ratio of 15:1, we would then predict a carrier
frequency of 0.09% for the Q347X mutation in the AJ
population. With this carrier frequency, out of 4,290 subjects
screened for this mutation, we would have expected 4 carriers
Poisson distribution forthe number ofcarriers, the probability
of observing none out of 4,290 when four are expected is 0.018.
Thus, it appears that the frequency of the Q347X allele in the
AJ population is probably lower than what might have been
predicted based on the data from the previously reported
that among 30 AJ patients screened in this study, all were
homozygous for the R83C mutation, i.e., 60 out of 60 AJ alleles
were R83C. One possible explanation for the discrepancy with
a previous study [Lei et al., 1995] is that the two compound
heterozygote patients observed in that study were of mixed
ancestry (i.e., less than 100% AJ), allowing the introduction of
any event, our data provide a compelling argument that R83C
is the only prevalent GSDIa mutation in the AJ population.
Also of interest is our estimated frequency for the R83C
mutation in the AJ population, namely 0.7%. This frequency
translates into an estimated disease prevalence of 1 in 20,000,
which is 5 times higher than the rate suggested for the
general Caucasian population. Thus, ourdata alsosupport the
presence of a founder effect for the R83C mutation that has
given rise to an elevated frequency of GSD1a in the AJ
population. We note that this mutation frequency is compar-
able or greater than those for a number of diseases currently
undergoing population screening in the AJ population, includ-
ing Niemann–Pick disease (0.5%) and Fanconi anemia (0.6%)
[Risch et al., 2003].
Genetic prenatal screening has classically focused on early
improving and many patients are now surviving into adult-
hood, there is still significant morbidity associated with the
disease. Severe hypoglycemia can occur within minutes, and
constant care, particularly of infants and young children, is
required. Frequent exposure to hypoglycemia can lead to
borderline mental development (IQ between 65 and 85) in 18%
of patients [Rake et al., 2002]. Seizures, hepatic adenomas,
hepatocellular carcinoma, and renal failure are all common
GSDIa in the AJ population, which is facilitated by homo-
geneity for the R83C mutation, may still be warranted and at
least requires further discussion.
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TABLE I. Results of Mutation Testing for Glycogen Storage
Disease Type Ia (GSDIa) in the Ashkenazi Population
MutationNumber testedNumber (%) carriers
GSDIa in the Ashkenazi Population163
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164Ekstein et al.