Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females.
Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
Giorda
Roberto
R
Biologia Molecolare, Eugenio Medea Scientific Institute, Bosisio Parini, LC, Italy. roberto.giorda@bp.lnf.it
Bonaglia
M Clara
MC
Beri
Silvana
S
Fichera
Marco
M
Novara
Francesca
F
Magini
Pamela
P
Urquhart
Jill
J
Sharkey
Freddie H
FH
Zucca
Claudio
C
Grasso
Rita
R
Marelli
Susan
S
Castiglia
Lucia
L
Di Benedetto
Daniela
D
Musumeci
Sebastiano A
SA
Vitello
Girolamo A
GA
Failla
Pinella
P
Reitano
Santina
S
Avola
Emanuela
E
Bisulli
Francesca
F
Tinuper
Paolo
P
Mastrangelo
Massimo
M
Fiocchi
Isabella
I
Spaccini
Luigina
L
Torniero
Claudia
C
Fontana
Elena
E
Lynch
Sally Ann
SA
Clayton-Smith
Jill
J
Black
Graeme
G
Jonveaux
Philippe
P
Leheup
Bruno
B
Seri
Marco
M
Romano
Corrado
C
dalla Bernardina
Bernardo
B
Zuffardi
Orsetta
O
D041321:Chromosomes, Human, X / Q000235:genetics*; D004569:Electroencephalography; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics*; D007805:Language Development Disorders / Q000150:complications* / Q000235:genetics*; D008297:Male; D010375:Pedigree