Hum Genet (1992) 88 : 599-600

9 Springer-Verlag1992

Letters to the editors

Selective advantage of fra(X) heterozygotes compared with mothers of Down syndrome probands? P. H . J o n g b l o e t 1'2

1Department of Epidemiology, Nijmegen University, The Netherlands 2Institute of Human Genetics, Free University, Amsterdam, The Netherlands Received April 16, 1991

In their very interesting paper, Vogel et al. (1990) have tested their hypothesis that (unaffected) women who are heterozygous for the fragile X (fra[X]) allele have a higher rate of reproduction than comparable women of the same generation. They eagerly searched for adequate control families and, having explored some alternatives, they finally decided in favour of Down syndrome (DS) mothers, their sisters and parents. Their decision, however, is questionable because DS mothers, aunts and maternal grandmothers do not appear to be representative of the general population with regard to fecundity. Admittedly, not all researches agree on maternal subfecundity in DS mothers (Smith and Record 1955; Cowie and Slater 1968), particularly when looking at fertility rates rather than at constitutional (see point 1, below) and fecundability characteristics, as manifested by recurrent pregnancy wastage (see points 2-7). 1. DS mothers apparently have a particular constitution predisposing to nondisjunction as evidenced by deviant dermatoglyphics (Schmidt et al. 1981), smaller stature (Harlap and Davies 1978), endocrine disturbances (Heinonen et al. 1977), accelerated ageing (Emanuel et al. 1972) and propensity to cancer (K~illen 1988). 2. Their reproductive history reveals a higher risk of nondisjunction after recurrent abortions and stillbirths ( H o o k and Cross 1983). 3. They appear to have a 10-fold increased risk of having another child with DS or other aneuploidy (FitzPatrick and Boyd 1989). 4. They share a predisposition to double ovulation (Kucera 1971; MacGillivray et al. 1988) and to having children with idiopathic mental retardation, congenital malformations and malignancy (Kaplan and Zsako 1970), such as leukaemia (Kucera 1971). 5. They experience longer waiting times before the DS pregnancy compared with other siblings or with similar Offprint requests to: P.H.Jongbloet, Maria Roepaan Centre for the Mentally Handicapped, Siebengewaldseweg 15, NL-6595 NX Ottersum, The Netherlands

controls (Juberg et al. 1973). This phenomenon is compatible with the more pronounced seasonality of DS births (Harlap 1974; Jongbloet and Vrieze 1985), indicating the more "seasonally conceiving tendency" of these mothers. 6. Apparently, they themselves have been more frequently conceived at a more advanced grandmaternal age, independent of the maternal age at the probands' conception (Aagesen et al. 1984). 7. They seem to have been more frequently conceived during spring and autumn (Jongbloet 1975; Kanai and Nakamura 1987), implying a constellation of subfecundity traits, with grandmothers being "seasonal" rather than "regular conceivers" (Jongbloet 1990). These constitutional and reproductive characteristics at least question the legitimacy of taking mothers and maternal grandmothers as a control group. The same holds for the maternal siblings, i.e. in view of other reproductive casualities related to seasonality of birth (Hare 1976; McNeil et al. 1976), as seems to be confirmed by grandmaternal subfecundity. Therefore, the conclusion of Vogel et al. (1990) that the increased fitness of (unaffected) heterozygous fra(X) females has been directly demonstrated seems premature. In consequence, the hypothesised selective advantage caused by increased reproduction of clinically unaffected carrier females, although attractive and probable, remains unproven. References

Aagesen L, Grinsted J, Mikkelsen M (1984) Advanced grandmaternal age on the mother's side - a risk of giving rise to trisomy 21. Ann Hum Genet 48:297-301 Cowie V, Slater E (1968) The fertility of mothers of mongols. J Ment Defic Res 12:196-208 Emanuel I, Sever LE, Milham S, Thuline HC (1972) Accelerated ageing in young mothers of children with Down's syndrome. Lancet II : 361-363 FitzPatrick DR, Boyd E (1989) Recurrences of trisomy 18 and trisomy 13 after trisomy 21. Hum Genet 82 : 301 Hare EH (1976) The season of birth of siblings of psychiatric patients. Br J Psychiatry 129 : 49-54

600 Harlap S (1974) A time series analysis of the incidence of Down's syndrome in West Jerusalem. Am J Epidemiol 99 : 210-217 Harlap S, Davies AM (1978) The pill and births: the Jerusalem study. Natl Inst Child Health Hum Dev, Table XII. Bethesda, MD Heinonen OP, Slone D, Shapiro S (1977) Birth defects and drugs in pregnancy. Publ Sc Group Inc, Littleton, MA, pp 223-231 Hook EB, Cross PK (1983) Spontaneous abortion and subsequent Down syndrome live birth. Hum Genet 64:267-270 Jongbloet PH (1975) The effects of pre-ovulatory overripeness of human eggs on development. In: Blandau RJ (ed) Aging gametes. Int Symp Seattle. Karger, Basel pp 300-329 Jongbloet PH, Vrieze OJ (1985) Down syndrome: increased frequency of maternal meiosis I nondisjunction during the transitional stages of ovulatory seasons. Clin Genet 28 : 439-440 Jongbloet PH (1990) Ovulation and season - vitality and monthof-birth. PUDOC, Wageningen, pp 143-158 Juberg RC, Goshen CR, Sholte FG (1973) Socioeconomic and reproductive characteristics of the parents of patients with the Gl trisomy syndrome. Soc Biol 20 : 404-415 K~illen B (1988) Down's syndrome and maternal cancer. A preliminary study. APMIS 96 : 168-170

Kanai H, Nakamura I (1987) Congenital malformations by month of birth. Prog Biometeorol 6: 123-130 Kaplan AR, Zsako S (1970) Biological variables associated with mothers of children affected with the Gi-trisomy syndrome (Down's syndrome). Am J Ment Defic 74 : 745-755 Kucera J (1971) Leukaemia and twinning tendency in families of children with Down's syndrome. J Ment Defic Res 15 : 77-80 MacGillivray I, Samphier M, Little J (1988) Factors affecting twinning. In: MacGillivray I, Campbell DM, Thompson B (eds) Twinning and twins. Wiley, NewYork, pp 67-98 McNeil T, Kaij L, Dzierzyvray-Rogalska M (1976) Season of birth among siblings of schizophrenics. Acta Psychiatr Scand 54: 267-274 Schmidt R, Hanna Dar, Nitowsky HM (1981) Dermatoglyphic and cytogenetic studies in parents of children with trisomy 21. Clin Genet 20 : 203-210 Smith A, Record RG (1955) Fertility and reproductive history of mothers of mongoloid defective. Br J Prevent Soc Med 9:8996 Vogel F, Crusio WE, Kovac C, Fryns J-P, Freund M (1990) Selective advantage of fra(X) heterozygotes. Hum Genet 86:25-32

Selective advantage of fra (X) heterozygotes compared with mothers of Down syndrome probands?

Hum Genet (1992) 88 : 599-600 9 Springer-Verlag1992 Letters to the editors Selective advantage of fra(X) heterozygotes compared with mothers of Dow...
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