Abstract
The finding of maternal uniparental disomy for chromosome 7 (matUPD7) in approximately 7% of Silver-Russell syndrome (SRS) cases has lead to the assumption that imprinted gene(s) on chromosome 7 are responsible for at least some cases. However, the observation in a familial case that both maternal and paternal inheritance of proximal 7p results in an SRS-like phenotype suggests that the causative genes may not be imprinted, and that an extra copy of genes within this region cause SRS. As all cases of complete matUPD7 could have arisen by trisomy rescue, it is possible that undetected trisomy 7 mosaicism contributes towards the phenotype of SRS, and that the matUPD7 seen in some cases is a consequence of trisomy rescue. Previous studies in cases of trisomy rescue for a number of autosomes have shown a strong association with skewed X inactivation in diploid tissues. Thus, we hypothesised that if trisomy mosaicism was involved in SRS, the frequency of skewed X inactivation should be increased in a population of non-matUPD7 SRS patients. Consistent with this hypothesis, results showed a significant increase in the frequency of completely skewed X inactivation in SRS patients (three of 29) when compared to controls (three of 270), suggesting the possible presence of undetected trisomy 7 in SRS patients and/or their placentas.
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References
Wakeling EL, Abu-Amero S, Price SM et al. Genetics of Silver-Russell syndrome Horm Res 1998 49: 32–36
Kotzot D, Schmitt S, Bernasconi F et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation Hum Mol Genet 1995 4: 583–587
Eggermann T, Wollmann HA, Kuner R et al. Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy Hum Genet 1997 100: 415–419
Preece MA, Price SM, Davies V et al. Maternal uniparental disomy 7 in Silver-Russell syndrome J Med Genet 1997 34: 6–9
Joyce CA, Sharp A, Walker JM, Bullman H, Temple IK . Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome Hum Genet 1999 105: 273–280
Monk D, Wakeling EL, Proud V et al. Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome Am J Hum Genet 2000 66: 36–46
Martinez MJ, Binkert F, Schinzel A, Kotzot D . No evidence of dup(7)(p11.2p13) in Silver-Russell syndrome Am J Med Genet 2001 99: 335–337
Abu-Amero S, Price S, Wakeling E et al. Lack of hemizygosity for the insulin-like growth factor I receptor gene in a quantitative study of 33 Silver Russell syndrome probands and their families Eur J Hum Genet 1997 5: 235–241
Rieswijk AM, Blagitko N, Schinzel AA et al. Evidence against a major role of Peg1/MEST in Silver-Russell syndrome Eur J Hum Genet 1998 6: 114–120
Eggermann K, Wollmann HA, Tomiuk J, Ranke MB, Kaiser P, Eggermann T . Screening for mutations in the promotor and the coding regions of the IGFBP1 and IGFBP3 genes in Silver-Russell syndrome patients Hum Hered 1999 49: 123–128
Mergenthaler S, Eggermann K, Tomiuk J, Ranke MB, Wollmann HA, Eggermann T . Exclusion of a disease relevant role of PAX4 in the aetiology of Silver-Russell syndrome: screening for mutations and determination of imprinting status J Med Genet 2000 37: E44
Mergenthaler S, Hitchins MP, Blagitko-Dorfs N et al. Conflicting reports of imprinting status of human GRB10 in developing brain: how reliable are somatic cell hybrids for predicting allelic origin of expression? Am J Hum Genet 2001 68: 543–545
Eggermann T, Kloos P, Mergenthaler S et al. IRS1 and GRB2 as members of the IGF signal transduction pathway are not associated with intrauterine growth retardation and Silver-Russell syndrome Clin Genet 2001 59: 371–373
Mergenthaler S, Wollmann HA, Burger B et al. Formation of uniparental disomy 7 delineated from new case and a UPD7 case after trisomy rescue. Presentation of own results and a review of the literature Ann Genet 2000 43: 15–21
Lau AW, Brown CJ, Penaherrera M, Langlois S, Kalousek DK, Robinson WP . Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicim Am J Hum Genet 1997 61: 1353–1361
Kotzot D, Balmer D, Baumer A et al. Maternal uniparental disomy 7 – review and further delineation of the phenotype Eur J Paediatr 2000 159: 247–256
Spence JE, Persiaccante RG, Greig GM et al. Uniparental disomy as a mechanism for human genetic disease Am J Hum Genet 1988 42: 217–226
Penaherrera MS, Barrett IJ, Brown CJ et al. An association between skewed X-chromosome inactivation and abnormal outcome in mosaic trisomy 16 confined predominantly to the placenta Clin Genet 2000 58: 436–446
Wollmann HA, Kirchner T, Enders H, Preece MA . Growth and symptoms in Silver-Russell syndrome: review on the basis of 386 patients Eu J Paediatr 1995 154: 958–968
Sharp A, Robinson D, Jacobs P . Age- and tissue-specific variation of X-chromosome inactivation ratios in normal women Hum Genet 2000 107: 343–349
Hannula K, Lipsanen-Nyman M, Kontiokari T, Kere J . A narrow segment of maternal uniparental disomy of chromosome 7q31-qter in Silver-Russell syndrome delimits a candidate gene region Am J Hum Genet 2001 68: 247–253
Risch N, Stein Z, Kline J, Warburton D . The relationship between maternal age and chromosome size in autosomal trisomy Am J Hum Genet 1986 39: 68–78
Hassold T, Merrill M, Adkins K, Freeman S, Sherman S . Recombination and maternal-age dependent nondisjunction: molecular studies of trisomy 16 Am J Hum Genet 1995 57: 867–874
Robinson WP, Barrett IJ, Bernard L et al. Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblast, and increased risk of fetal intrauterine growth restriction Am J Hum Genet 1997 60: 917–927
Duncan PA, Hall JG, Shapiro LR, Vibert BK . Three generation dominant transmission of the Silver-Russell syndrome Am J Med Genet 1990 35: 245–250
Kalousek DK, Langlois S, Barrett I et al. Uniparental disomy for chromosome 16 in humans Am J Hum Genet 1993 52: 8–16
Chauvel PJ, Moore CM, Haslam RH . Trisomy 18 mosaicism with features of Russell-Silver syndrome Dev Med Child Neurol 1975 17: 220–224
Monk D, Hitchins M, Russo S, Preece M, Stanier P, Moore GE . No evidence for mosaicism in Silver-Russell syndrome J Med Genet 2001 38: E11
Fryns, JP . Chromosome 7, mosaic trisomy 7 in: Buyse ML (ed): Birth Defects Encyclopaedia Cambridge, MA 1990 vol 1: p 348
Miyoshi O, Kondoh T, Taneda H, Otsuka K, Matsumoto T, Niikawa N . 47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative gene from a 7p13-q11 region J Med Genet 1999 36: 326–329
Hoglund P, Holmberg C, de la Chapelle A, Kere J . Paternal isodisomy for chromosome 7 is compatible with normal growth and development in a child with congenital chloride diarrhea Am J Hum Genet 1994 55: 747–752
Pan Y, McCaskill CD, Thompson KH et al. Paternal isodisomy of chromosome 7 associated with complete situs inversus and immotile cilia Am J Hum Genet 1998 62: 1551–1555
Acknowledgements
The authors would like to thank Prof Michael Preece (Institute of Child Health, London), Dr Sue Price (Northampton General Hospital NHS Trust), and Dr Hartmut Wollmann (Childrens Hospital, University of Tuebingen, Germany) for the referral of patients used in this study. We would also like to thank Prof Patricia Jacobs for helpful discussion and advice during the preparation of this manuscript, and Paul Strike for assistance with statistical analyses. Andrew Sharp is supported by a Wellcome Trust PhD Prize Studentship (Ref. 058387).
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Sharp, A., Moore, G. & Eggermann, T. Evidence from skewed X inactivation for trisomy mosaicism in Silver-Russell syndrome. Eur J Hum Genet 9, 887–891 (2001). https://doi.org/10.1038/sj.ejhg.5200740
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DOI: https://doi.org/10.1038/sj.ejhg.5200740
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