Elisa Scala1, Ilaria Longo1, Federica Ottimo1, Caterina Speciale1, Katia Sampieri1, Eleni Katzaki1, Rosangela Artuso1, Maria Antonietta Mencarelli1, Tatiana D'Ambrogio2, Giuseppina Vonella2, Michele Zappella2, Joussef Hayek2, Agatino Battaglia3, Francesca Mari1, Alessandra Renieri1, Francesca Ariani1
1Medical Genetics Molecular Biology Department, University of Siena, Siena, Italy
2Infantile Neuropsychiatry, Siena General Hospital, Siena, Italy
3Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Pisa, Italy
Tóm tắt
AbstractRett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2–4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation‐negative Rett patients (33 classic, 31 variant, and 13 Rett‐like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one “highly functioning” preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2‐negative patients, especially in those more severely affected (P = 0.044). © 2007 Wiley‐Liss, Inc.
