Two sisters with Rett syndrome and non-identical paternally-derived microdeletions in the MECP2 gene

Lyndon G. Rosser1, Shane McKee2, David S. Millar3, Hayley Archer1, James Hughes4, Rachel Butler1, Nadia Chuzhanova5, David N. Cooper3, Lazarus P. Lazarou1
1Institute of Medical Genetics, Cardiff and Vale NHS Trust, University Hospital of Wales, Cardiff, UK
2Department of Medical Genetics, Belfast City Hospital, Belfast, UK
3Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
4University Department of Paediatrics, Daisy Hill Hospital, Newry, UK
5School of Computing, Engineering and Physical Sciences, University of Central Lancashire, Preston, UK

Tóm tắt

The unique case of two sisters with symptoms of RTT and two quite distinct, novel, and apparently de novo microdeletions of the MECP2 gene is described. One sister possessed an 18 base-pair (bp) deletion (c.1155_1172del18) within the deletion hotspot region of exon 4, whereas the other sister exhibited a 43 bp deletion at a different location in the same exon (c.1448_1461del14+29). Although these lesions occurred on the same paternally-derived X chromosome, this is probably due to chance co-occurrence owing to the relatively high mutation rate of the MECP2 gene rather than to a constitutional mutator phenotype.

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Tài liệu tham khảo

Amir RE, Van den Veyver I, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188. doi:10.1038/13810

Archer H, Evans J, Leonard H, Colvin L, Ravine D, Christodoulou J, Williamson S, Charman T, Bailey MES, Sampson J, de Klerk N, Clarke A (2007) Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. J Med Genet 44:148–152

Bienvenu T, Chelly J (2006) Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nat Rev Genet 7:415–426. doi:10.1038/nrg1878

Chahrour M, Zoghbi HY (2007) The story of Rett syndrome: from clinic to neurobiology. Neuron 56:422–437. doi:10.1016/j.neuron.2007.10.001

Cheadle JP, Gill H, Fleming N, Maynard J, Kerr A, Leonard H et al (2000) Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet 9:1119–1129. doi:10.1093/hmg/9.7.1119

Davidson S, Leshanski L, Rennert G, Eidelman S, Amikam D (2002) Maternal mosaicism for a second mutational event—a novel deletion—in a familial adenomatous polyposis family harbouring a new germ-line mutation in the alternatively spliced exon 9 region of APC. Hum Mutat 19:83–84. doi:10.1002/humu.9006

Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA et al (2007) MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev 29:47–50. doi:10.1016/j.braindev.2006.06.001

Evans JC, Archer HL, Whatley SD, Clarke A (2006) Germline mosaicism for a MECP2 mutation in a man with two Rett daughters. Clin Genet 70:336–338. doi:10.1111/j.1399-0004.2006.00691.x

Fan G, Hutnick L (2005) Methyl-CpG binding proteins in the nervous system. Cell Res 15:255–261. doi:10.1038/sj.cr.7290294

Gusev VD, Nemytikova LA, Chuzhanova NA (1999) On the complexity measures of genetic sequences. Bioinformatics 15:994–999. doi:10.1093/bioinformatics/15.12.994

Hardwick SA, Reuter K, Williamson SL, Vasudevan V, Donald J, Slater K et al (2007) Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband. Eur J Hum Genet 15:1218–1229. doi:10.1038/sj.ejhg.5201911

Huppke P, Gärtner J (2005) Molecular diagnosis of Rett syndrome. J Child Neurol 20:732–736

Klose A, Peters H, Hoffmeyer S, Buske A, Luder A, Hess D et al (1999) Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet 83:6–12. doi:10.1002/(SICI)1096-8628(19990305)83:1<6::AID-AJMG3>3.0.CO;2-E

Knudsen GP, Neilson TC, Pedersen J, Kerr A, Schwartz M, Hulten M et al (2006) Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers. Eur J Hum Genet 14:1189–1194. doi:10.1038/sj.ejhg.5201682

Laing NG, Layton MG, Johnsen RD, Chandler DC, Mears ME, Goldblatt J et al (1992) Two distinct mutations in a single dystrophin gene: chance occurrence or premutation? Am J Med Genet 42:688–692. doi:10.1002/ajmg.1320420512

Mari F, Caselli R, Russo S, Cogliati F, Ariani F, Longo I et al (2005) Germline mosaicism in Rett syndrome identified by prenatal diagnosis. Clin Genet 67:258–260. doi:10.1111/j.1399-0004.2005.00397.x

Miltenberger-Miltenyi G, Laccone F (2003) Mutations and polymorphisms in the human methyl CpG-binding protein MECP2. Hum Mutat 22:107–115. doi:10.1002/humu.10243

Mnatzakanian GN, Lohi H, Munteanu I, Alfred SE, Yamada T, MacLeod PJ et al (2004) A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet 36:339–341. doi:10.1038/ng1327

Morandi L, Mora M, Tedeschi S, Di Blasi C, Curcio C, De Leonardis P et al (1995) DMD and BMD in the same family due to distinct mutations. Am J Med Genet 59:501–505. doi:10.1002/ajmg.1320590418

Mostacciuolo ML, Miorin M, Vitiello L, Rampazzo A, Fanin M, Angelini C et al (1994) Occurrence of two different intragenic deletions in two male relatives affected with Duchenne muscular dystrophy. Am J Med Genet 50:84–86. doi:10.1002/ajmg.1320500118

Munier FL, Wang MX, Spence MA, Thonney F, Balmer A, Pescia G et al (1993) Pseudo low penetrance in retinoblastoma. Fortuitous familial aggregation of sporadic cases caused by independently derived mutations in two large pedigrees. Arch Ophthalmol 111:1507–1511

Percy AK (2002) Rett syndrome. Current status and new vistas. Neurol Clin 20:1125–1141. doi:10.1016/S0733-8619(02)00022-1

Philippe C, Villard L, De Roux N, Raynaud M, Bonnefond JP, Pasquier L et al (2006) Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet 49:9–18. doi:10.1016/j.ejmg.2005.04.003

Tizzano EF, Venceslá A, Baena M, Cornet M, Calvo MT, Lucía JF et al (2005) First report of two independent point factor VIII mutations in a family with haemophilia A: a word of caution for carrier diagnosis. Thromb Haemost 94:675–677

Trappe R, Laccone F, Cobilanschi J, Meins M, Huppke P, Hanefeld F et al (2001) MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet 68:1093–1101. doi:10.1086/320109

Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M et al (2003) Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet 112:12–17. doi:10.1007/s00439-002-0840-1

Venâncio M, Santos M, Pereira SA, Maciel P, Saraiva JM (2007) An explanation for another familial case of Rett syndrome: maternal germline mosaicism. Eur J Hum Genet 15:902–904. doi:10.1038/sj.ejhg.5201835

Villard L, Kpebe A, Cardoso C, Chelly PJ, Tardieu PM, Fontes M (2000) Two affected boys in a Rett syndrome family: clinical and molecular findings. Neurology 55:1188–1193

Villard L, Lévy N, Xiang F, Kpebe A, Labelle V, Chevillard C, Zhang Z, Schwartz CE, Tardieu M, Chelly J, Anvret M, Fontès M (2001) Segregation of a totally skewed pattern of X chromosome inactivation in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease. J Med Genet 38:435–442

Wang G, Vasquez KM (2006) Non-B DNA structure-induced genetic instability. Mutat Res 598:103–119. doi:10.1016/j.mrfmmm.2006.01.019

Weaving LS, Ellaway CJ, Gécz J, Christodoulou J (2005) Rett syndrome: clinical review and genetic update. J Med Genet 42:1–7. doi:10.1136/jmg.2004.027730

Williamson SL, Christodoulou J (2006) Rett syndrome: new clinical and molecular insights. Eur J Hum Genet 14:896–903. doi:10.1038/sj.ejhg.5201580

Zatz M, Sumita D, Campiotto S, Canovas M, Cerqueira A, Vainzof M et al (1998) Paternal inheritance or different mutations in maternally related patients occur in about 3% of Duchenne familial cases. Am J Med Genet 78:361–365. doi:10.1002/(SICI)1096-8628(19980724)78:4<361::AID-AJMG11>3.0.CO;2-G