American Journal of Medical Genetics 40523 (1991)
Letter to the Editor
Risk Calculations in the Fragile-X Syndrome To the Editor:
In our experience in 50 out of 52 fragile-X families the fragile-X mutation could be shown to be nonsporadic: with frequent occurrence of so called “normal transmitting males” [Smits et al., manuscript in preparation]. Indeed, if we carry out a model risk calculation for this family with hnother fragile-X patient in either the maternal or paternal lineage, we arrive a t a risk of less than 1%. In addition, it is important to know which haplotype is found in the maternal grandfather, as this would be vital to the interpretation of the pedigree reported by van Roy et al. [19901. Finally we want t o urge for caution in the interpretation of DNA analysis in the absence of accurate phase determination. This is particularly relevant to the fragile-X syndrome where extended family studies may frequently demonstrate additional gene carriers.
We have read with interest the article of van Roy et al. [19901 concerning 2 brothers with mental retardation discordant for the fragile-X syndrome. The authors argue that this can be explained by the finding that the brothers each inherited a different X chromosome from their mother. This conclusion was based on the RFLP analysis of 2 proximal DNA markers (F9, DXS98) and 3 distal markers (DXS52, DXS15, and F8). No recombinants between these markers were found in this pedigree. Because flanking DNA markers were used with recombination fractions of 6 and 13 cM the authors state that the chance of a double crossover is less than 1%and hence the chance that the mentally retarded fragile-X negative brother might still carry the fragile-X gene is less than 1%. REFERENCES We have recalculated the risk of the fragile-X nega- Lathrop GM, Lalouel JM (1984): Easy calculations of lod scores and tive brother with the LINKAGE computer program genetic risks on small computers. Am J Hum Genet 36:460-465. [Version 5.03, Lathrop and Lalouel, 19841. We used all Sherman SL, Morton NE, Jacobs PA, Turner G (1984):The marker X pedigree data and the DNA data for the closest flanking syndrome: A cytogenetic and genetic analysis. Ann Hum Genet 48:21-37. markers, DXS98 and DXS15, as given by van Roy et al. [19901. The penetrance in females was taken as 0.56 and Sherman SL, Jacobs PA, Morton NE, Roster-Iskenius K, HowardPeedbles PV, Nielsen KB, Patington MW, Sutherland GR, Turner in males as 0.8, while the gene frequency was estimated G, Watson M (1985):Further segregation analysis of the fragile-X to be 0.001 [Sherman et al., 1984,19851.We arrive a t a syndrome with special reference to transmitting males. Hum Genet 69:289-299. risk of 3.5% assuming no new mutations. If we take a mutation rate of 1/2,000the risk for the cytogenetically van Roy BC, Willems PJ, Vits U,Ceulemans BP, Coucke PJ, van de Auwera BJ, Lormans JAG, Dumon J E (1990): Two brothers with negative male to carry the fragile-X mutation still exmental retardation discordant for the fragile-X syndrome. Am J ceeds 1%. Med Genet 36:122-125. This discrepancy is easily explained by the fact that only one patient has been ascertained in this family and Joseph C.F.M. Dreesen that marker data are given for individuals in 2 generaArie Smits tions only. Therefore the phase (the DNA marker alleles Han Brunner with which the fragile-X gene segregates) cannot be Department of Human Genetics accurately defined because the chance of a single recomUniversity Hospital Nijmegen binant between the flanking DNA markers is in the Nijmegen, The Netherlands order of 20%.
Received for publication September 7, 1990. Address reprint requests to Joseph C.F.M. Dreesen, Department of Human Genetics-M307, University Hospital Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands.
0 1991 Wiley-Liss, Inc.
Letter to the Editor
Risk Calculations in the Fragile-X Syndrome To the Editor:
In our experience in 50 out of 52 fragile-X families the fragile-X mutation could be shown to be nonsporadic: with frequent occurrence of so called “normal transmitting males” [Smits et al., manuscript in preparation]. Indeed, if we carry out a model risk calculation for this family with hnother fragile-X patient in either the maternal or paternal lineage, we arrive a t a risk of less than 1%. In addition, it is important to know which haplotype is found in the maternal grandfather, as this would be vital to the interpretation of the pedigree reported by van Roy et al. [19901. Finally we want t o urge for caution in the interpretation of DNA analysis in the absence of accurate phase determination. This is particularly relevant to the fragile-X syndrome where extended family studies may frequently demonstrate additional gene carriers.
We have read with interest the article of van Roy et al. [19901 concerning 2 brothers with mental retardation discordant for the fragile-X syndrome. The authors argue that this can be explained by the finding that the brothers each inherited a different X chromosome from their mother. This conclusion was based on the RFLP analysis of 2 proximal DNA markers (F9, DXS98) and 3 distal markers (DXS52, DXS15, and F8). No recombinants between these markers were found in this pedigree. Because flanking DNA markers were used with recombination fractions of 6 and 13 cM the authors state that the chance of a double crossover is less than 1%and hence the chance that the mentally retarded fragile-X negative brother might still carry the fragile-X gene is less than 1%. REFERENCES We have recalculated the risk of the fragile-X nega- Lathrop GM, Lalouel JM (1984): Easy calculations of lod scores and tive brother with the LINKAGE computer program genetic risks on small computers. Am J Hum Genet 36:460-465. [Version 5.03, Lathrop and Lalouel, 19841. We used all Sherman SL, Morton NE, Jacobs PA, Turner G (1984):The marker X pedigree data and the DNA data for the closest flanking syndrome: A cytogenetic and genetic analysis. Ann Hum Genet 48:21-37. markers, DXS98 and DXS15, as given by van Roy et al. [19901. The penetrance in females was taken as 0.56 and Sherman SL, Jacobs PA, Morton NE, Roster-Iskenius K, HowardPeedbles PV, Nielsen KB, Patington MW, Sutherland GR, Turner in males as 0.8, while the gene frequency was estimated G, Watson M (1985):Further segregation analysis of the fragile-X to be 0.001 [Sherman et al., 1984,19851.We arrive a t a syndrome with special reference to transmitting males. Hum Genet 69:289-299. risk of 3.5% assuming no new mutations. If we take a mutation rate of 1/2,000the risk for the cytogenetically van Roy BC, Willems PJ, Vits U,Ceulemans BP, Coucke PJ, van de Auwera BJ, Lormans JAG, Dumon J E (1990): Two brothers with negative male to carry the fragile-X mutation still exmental retardation discordant for the fragile-X syndrome. Am J ceeds 1%. Med Genet 36:122-125. This discrepancy is easily explained by the fact that only one patient has been ascertained in this family and Joseph C.F.M. Dreesen that marker data are given for individuals in 2 generaArie Smits tions only. Therefore the phase (the DNA marker alleles Han Brunner with which the fragile-X gene segregates) cannot be Department of Human Genetics accurately defined because the chance of a single recomUniversity Hospital Nijmegen binant between the flanking DNA markers is in the Nijmegen, The Netherlands order of 20%.
Received for publication September 7, 1990. Address reprint requests to Joseph C.F.M. Dreesen, Department of Human Genetics-M307, University Hospital Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, The Netherlands.
0 1991 Wiley-Liss, Inc.
