Hum Genet (1985) 69:289-299 Original investigations Further segregation analysis of the fragile X syndrome with special reference to transmitting males © Springer-Verlag 1985 S. L. Sherman 1, P. A. Jacobs 2, N. E. Morton 1, U. Froster-Iskenius 3, P. N. Howard-Peebles 4, K.B. Nielsen 5, M. W. Partington 6, G. R. Sutherland 7, G. Turner 8, and M. Watson 9 i Population Genetics Laboratory, University of Hawaii, 1980 East-West Rd., Honolulu, HI 96822, USA 2 Department of Anatomy and Reproductive Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96822, USA 3 Institut ftir Humangenetik, Lfibeck, Ratzeburger Allee 160, D-2400 Lfibeck 4 Department of Pathology, University of Texas Health Science Center at Dallas, Dallas, TX 75235, USA 5 Department of Medical Genetics, The John F. Kennedy Institute, Glostrup, Denmark 6 Department of Paediatrics, Queens University, Kingston, Ontario, Canada 7 Cytogenetics Unit, Department of Histopathology, Adelaide Children's Hospital, North Adelaide S.A., 5006 Australia s The Prince of Wales Children's Hospital, Randwick, N.S.W., Australia 9 Department of Human Genetics, Yale University, School of Medicine, New Haven, CT 06510, USA Summary. A new series of 96 pedigrees with the fra(X) syn- drome was analysed using complex segregation analysis with pointers, defining affection as any degree of mental impair- ment. These families were found to exhibit the same segrega- tion pattern as the first series of 110 pedigrees (Sherman et al. 1984). The best estimate for penetrance of mental impairment in males was 79% and in females was 35% for the combined data. Again, there was little evidence for sporadic cases among affected males. Many more intellectually normal transmitting males have been observed since the existence of such males and the con- comitant need to investigate the paternal side of pedigrees was recognized. On further investigation of all 206 pedigrees from the old and new data sets, the sibships of nonexpressing males appeared to be different from those of expressing males. Our analysis, using mental impairment as the phenotype, sug- gested that obligate carrier mothers and daughters of intellec- tually normal transmitting males are rarely, if ever, mentally impaired and that the sibs of transmitting males are much less likely to be retarded than the sibs of mentally impaired males. Though mothers and daughters of transmitting males are sim- ilar in phenotype, the expression of the gene in their offspring appears to be different: the penetrance of mental impairment is higher in offspring of intellectually normal daughters of transmitting males than in offspring of intellectually normal mothers of transmitting males. The implications of these ob- servations for genetic counseling and for genetic models of the fra(X) syndrome are discussed. Introduction The fra(X) syndrome is a familial X-linked form of mental retardation distinguished cytologically by a fragile site in band q27-28 of the X chromosome in cells of affected individuals. The actual relationship between the fra(X) site and the X- linked mental retardation is still unclear. Almost all overtly retarded males express the fragile site and vice versa. Prob- ably less than 1% of males with the gene express the fra(X) Offprint requests to: Dr. S. L. Sherman, Population Genetics Labora- tory, University of Hawaii, 1980 East-West Rd., Honolulu, HI 96822, USA and have an IQ in the normal range (Daker et al. 1981; Niel- sen et al. 1981; Webb et al. 1981; Sutherland 1982; Sherman et al. 1984). There are now many reports of males who are mentally normal and transmit the fra(X) gene to their daugh- ters and all who have been cytogenetically tested have been found to be fra(X) negative (Martin and Bell 1943; Dunn et al. 1963; Nielsen et al. 1981; Fryns and Van den Berghe 1982; Rhoads et al. 1982; Camerino et al. 1983; Gardner et al. 1983; Jacobs et al. 1983; Kahkonen et al. 1983; Van Roy et al. 1983). Thus, the fra(X) gene does not appear to be fully pene- trant in males and in this respect is different from all other known X-linked diseases. Females carrying the gene differ greatly in the degree of affection in regard to both mental impairment and fra(X) expression. Lyonization, or X-inactivation, could play a role in the variable expression (Froster-Iskenius et al. 1982; Howell and McDermott 1982; Nielsen et al. 1983; Uchida et al. 1983), however, the lack of expression in a proportion of females could be due to incomplete penetrance of the gene. About one-third of carriers are estimated to be mentally impaired (Turner et al. 1980; Fishburn et al. 1983; Sherman et al. 1984) but usually to a lesser degree than affected males, only a few being reported as moderately retarded. The fre- quency of the fra(X) positive cells in female carriers is in- versely correlated with IQ and intellectually normal females express at a low frequency or not at all. It has been estimated that approximately one-half of females carrying the gene can be detected by mental impairment and/or fra(X) expression (Sherman et al. 1984). Segregation analysis of the fra(X) syndrome includes defining an appropriate phenotype which can be reported with few biases, determining the prevalence of this phenotype in the population concerned, and estimating reproductive fitness of individuals with the syndrome. Ideally, all individuals in a family should be cytogenetically and psychometrically tested. Unfortunately, in many pedigrees only selected individuals are tested for fra(X) expression and IQ, thus neither trait is useful as a phenotype at this time. The most realistic pheno- type to use as a measure of affection is mental impairment of any degree. Since almost all males with the fra(X) are overtly retarded, problems in diagnosing this phenotype in males are not serious. However, diagnosing affected females is difficult