American Journal of M e d i c a l Genetics 44:389 (1992)
Letter to the Editor
Mutation Analysis in Gaucher Disease To The Editor The article by Sidransky et al. [1992] on DNA mutation analysis in Gaucher disease emphasizes the difficulty in making accurate phenotypic predictions from the genotype of a patient with Gaucher disease. This, indeed, has become a major problem, particularly as we have identified additional common Jewish mutations making possible population-based screening at the DNA level [Beutler, 1991; Beutler et al., 19921. In spite of the overlap between phenotypes, most patients homozygous for the mutation a t nt 1226l have mild, late onset disease. Although the data of Sidransky et al. [19921appear to show that the severity of Gaucher disease is the same in the 1226G/1226G,1226G/?,and 1226G/1448C genotypes, this is clearly because their ascertainment of 1226G homozygotes is quite incomplete. In their entire Ashkenazi sample of 18 patients, 53%of the disease-producing alleles were identified as a 1226 mutation, but only 3 homozygotes were found. Application of the Hardy-Weinberg equilibrium leads to the expectation that 5 patients would have been homozygotes for this genotype. With the small sample Sidransky et al. [19921have studied, this deviation from expectation has very low statistical significance, but examination of our much larger group of 109 Ashkenazi Jewish Gaucher disease samples confirms how underrepresented 1226G/1226G homozygotes are in their series. We found that 58 of 109 Ashkenazi Jewish patients were homozygous for this mutation and most had very mild disease. Why the difference in the incidence of the mild 1226G/1226Ggenotype in our populations? The pattern of referral of patients to our center apparently differs from that of the NIH. However, even the high frequency of 1226G11226G homozygotes that we observe represents an underestimate of the frequency of this genotype. We are now beginning to develop evidence that patients with this genotype include not only the occasional patients who are diagnosed late in life, but that a substantial proportion of patients homozygous for the
Received for publication March 6 , 1992. Address reprint requests to Dr. Ernest Beutler, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10666 N. Torrey Pines Road, La Jolla, CA 92037. ‘Designated by Sidransky at al. [19921 as Ser-370, based on the amino acid sequence of the processed protein. We prefer to use the cDNA nucleotide number because the nucleotide sequence, not the amino acid sequence, is actually determined and because the starting point is less ambiguous.
0 1992 Wiley-Liss, Inc.
1226 mutation actually are never diagnosed. We have been able to arrive at this conclusion by determining the frequency of the 1226 mutation and the second most common mutation, the 84GG mutation, in more than 1700 Ashkenazi Jewish subjects. Whereas the ratio of the 1226G:84GGgene frequencies in the patient population was 6.3:1, in the general population the ratio is 1O:l. Based on these data our current best estimate is that one-half to two-thirds of the patients with the 1226G/1226Ggenotype may have such mild disease that they never come to medical attention at all. The population data indicate that instead of 17% of Ashkenazi patients being homozygotes for the 1226 mutation as suggested by the clinical data of Sidransky et al. 119921 or even the 53% in our clinical series, 83%of all Jewish Gaucher disease patients have the 1226G/1226G genotype, and many of these have no clinical disease a t all. Indeed, out of 1792 Ashkenazi Jewish patients in a “normal” population, 4 were found to be homozygous for the 1226G mutation. A portion of this experience has been published [Zimran et al., 19911. Whereas it is obvious, then, that most patients with the 1226G/1226Ggenotype have very mild disease, contrary to the impression created by a highly selected patient population, there is no question that some have moderately severe disease, as we have documented consistently in our studies [Zimran et al., 1989; Beutler, 1991;Beutler et al., 19921. Determining the cause ofthis phenotypic variation is a major challenge.
REFERENCES Beutler E (1991): Gaucher’s disease. N Engl J Med 325:1354-1360. Beutler E, Gelbart T, Kuhl W, Zimran A, West C (1992):Mutations in Jewish patients with Gaucher disease. Blood 79:1662-1666, 1992. SidranskyE,TsqjiS,MartinBM, StubblefieldB,GinnsEI(1992):DNA mutation analysis of Gaucher patients. Am J Med Genet 42331-336. Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E (1991): High frequency of the 1226 mutation for type I Gaucher disease among the Ashkenazi Jewish population. Am J Hum Genet 49855-859. Zimran A, Sorge J, Gross E, Kubitz M, West C, Beutler E (1989): Prediction of severity of Gaucher’sdisease by identificationof mutations at DNA level. Lancet 2:349-352.
Ernest Beutler Terri Gelbart The Scripps Research Institute, La Jolla, California 29037
Letter to the Editor
Mutation Analysis in Gaucher Disease To The Editor The article by Sidransky et al. [1992] on DNA mutation analysis in Gaucher disease emphasizes the difficulty in making accurate phenotypic predictions from the genotype of a patient with Gaucher disease. This, indeed, has become a major problem, particularly as we have identified additional common Jewish mutations making possible population-based screening at the DNA level [Beutler, 1991; Beutler et al., 19921. In spite of the overlap between phenotypes, most patients homozygous for the mutation a t nt 1226l have mild, late onset disease. Although the data of Sidransky et al. [19921appear to show that the severity of Gaucher disease is the same in the 1226G/1226G,1226G/?,and 1226G/1448C genotypes, this is clearly because their ascertainment of 1226G homozygotes is quite incomplete. In their entire Ashkenazi sample of 18 patients, 53%of the disease-producing alleles were identified as a 1226 mutation, but only 3 homozygotes were found. Application of the Hardy-Weinberg equilibrium leads to the expectation that 5 patients would have been homozygotes for this genotype. With the small sample Sidransky et al. [19921have studied, this deviation from expectation has very low statistical significance, but examination of our much larger group of 109 Ashkenazi Jewish Gaucher disease samples confirms how underrepresented 1226G/1226G homozygotes are in their series. We found that 58 of 109 Ashkenazi Jewish patients were homozygous for this mutation and most had very mild disease. Why the difference in the incidence of the mild 1226G/1226Ggenotype in our populations? The pattern of referral of patients to our center apparently differs from that of the NIH. However, even the high frequency of 1226G11226G homozygotes that we observe represents an underestimate of the frequency of this genotype. We are now beginning to develop evidence that patients with this genotype include not only the occasional patients who are diagnosed late in life, but that a substantial proportion of patients homozygous for the
Received for publication March 6 , 1992. Address reprint requests to Dr. Ernest Beutler, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10666 N. Torrey Pines Road, La Jolla, CA 92037. ‘Designated by Sidransky at al. [19921 as Ser-370, based on the amino acid sequence of the processed protein. We prefer to use the cDNA nucleotide number because the nucleotide sequence, not the amino acid sequence, is actually determined and because the starting point is less ambiguous.
0 1992 Wiley-Liss, Inc.
1226 mutation actually are never diagnosed. We have been able to arrive at this conclusion by determining the frequency of the 1226 mutation and the second most common mutation, the 84GG mutation, in more than 1700 Ashkenazi Jewish subjects. Whereas the ratio of the 1226G:84GGgene frequencies in the patient population was 6.3:1, in the general population the ratio is 1O:l. Based on these data our current best estimate is that one-half to two-thirds of the patients with the 1226G/1226Ggenotype may have such mild disease that they never come to medical attention at all. The population data indicate that instead of 17% of Ashkenazi patients being homozygotes for the 1226 mutation as suggested by the clinical data of Sidransky et al. 119921 or even the 53% in our clinical series, 83%of all Jewish Gaucher disease patients have the 1226G/1226G genotype, and many of these have no clinical disease a t all. Indeed, out of 1792 Ashkenazi Jewish patients in a “normal” population, 4 were found to be homozygous for the 1226G mutation. A portion of this experience has been published [Zimran et al., 19911. Whereas it is obvious, then, that most patients with the 1226G/1226Ggenotype have very mild disease, contrary to the impression created by a highly selected patient population, there is no question that some have moderately severe disease, as we have documented consistently in our studies [Zimran et al., 1989; Beutler, 1991;Beutler et al., 19921. Determining the cause ofthis phenotypic variation is a major challenge.
REFERENCES Beutler E (1991): Gaucher’s disease. N Engl J Med 325:1354-1360. Beutler E, Gelbart T, Kuhl W, Zimran A, West C (1992):Mutations in Jewish patients with Gaucher disease. Blood 79:1662-1666, 1992. SidranskyE,TsqjiS,MartinBM, StubblefieldB,GinnsEI(1992):DNA mutation analysis of Gaucher patients. Am J Med Genet 42331-336. Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E (1991): High frequency of the 1226 mutation for type I Gaucher disease among the Ashkenazi Jewish population. Am J Hum Genet 49855-859. Zimran A, Sorge J, Gross E, Kubitz M, West C, Beutler E (1989): Prediction of severity of Gaucher’sdisease by identificationof mutations at DNA level. Lancet 2:349-352.
Ernest Beutler Terri Gelbart The Scripps Research Institute, La Jolla, California 29037
