Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location

Cheadle, Jeremy Peter ORCID: https://orcid.org/0000-0001-9453-8458, Gill, Harinder, Fleming, Nick, Maynard, Julie Helen, Kerr, Alison, Leonard, Helen, Krawczak, Michael, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484, Lynch, Sally, Thomas, Nicholas Stuart Tudor, Hughes, Helen, Hulten, Maj, Ravine, David, Sampson, Julian Roy ORCID: https://orcid.org/0000-0002-2902-2348 and Clarke, Angus John ORCID: https://orcid.org/0000-0002-1200-9286 2000. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Human Molecular Genetics 9 (7) , pp. 1119-1129. 10.1093/hmg/9.7.1119

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Abstract

Mutations in the methyl-CpG-binding protein gene MECP2 at Xq28 cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder characterized by a period of stagnation followed by regression in the development of young girls. Mutations were sought in MECP2 in 48 females with classical sporadic RTT, seven families with possible familial RTT and five sporadic females with features suggestive, but not diagnostic of RTT. Long distance PCR coupled with long-read direct sequencing was employed to sequence the entire MECP2 gene coding region in all cases. Mutations were identified in 44/55 (80%) unrelated classical sporadic and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT. Twenty-one different mutations were identified (12 missense, four nonsense and five frame-shift mutations); 14 of these were novel. All missense mutations were located either in the methyl-CpG-binding domain or in the transcription repression domain. Nine recurrent mutations were characterized in a total of 33 unrelated cases (73% of all cases with MECP2 mutations). Significantly milder disease was noted in patients carrying missense mutations as compared with those with truncating mutations (P = 0.0023), and milder disease was associated with late as compared with early truncating mutations (P = 0.0190).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Oxford University Press
ISSN:	0964-6906
Last Modified:	22 Jul 2023 01:13
URI:	https://orca.cardiff.ac.uk/id/eprint/59943

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