Duplication at Xq13.3-q21.1 With Syndromic Intellectual Disability, a Probable Role for the ATRX Gene

Autores de IIS La Fe

• Francisco Martinez Soriano

  Autor

• Mónica Pilar Roselló Piera

  Autor

• Sonia Mayo De Andres

  Autor

• Sandra Monfort Membrado

  Autor

• Juan Silvestre Oltra Soler

  Autor

• Carmen Orellana Alonso

  Autor

Grupos

• Investigación Traslacional en Genética

  

  Leader

  Francisco Martínez Castellano

Abstract

Here we report on two unrelated male patients with syndromic intellectual disability (ID) due to duplication at Xq13.3-q21.1, a region of about 6Mb and 25 genes. Among these, the most outstanding is ATRX, the causative gene of X-linked alpha-thalassemia/mental retardation. ATRX belongs to the growing list of genes implied in chromatin remodeling causing ID. Many these genes, such as MECP2, are dose-sensitive so that not only deletions and point mutations, but also duplications cause ID. Both patients have severe ID, absent expressive speech, early hypotonia, behavior problems (hyperactivity, repetitive self-stimulatory behavior), postnatal growth deficiency, microcephaly, micrognathia, cryptorchidism, low-set, posteriorly angulated ears, and downslanting palpebral fissures. These findings are also usually present among patients with loss-of-function mutations of the ATRX gene. Completely skewed X inactivation was observed in the only informative carrier mother, a constant finding among female carriers of inactivating point mutations of this gene. Participation of other duplicated genes cannot be excluded; nevertheless we propose that the increased dosage of ATRX is the major pathogenic mechanism of this X-linked disorder, a syndrome reminiscent of MECP2 duplication. (c) 2014 Wiley Periodicals, Inc.

Keywords

• XLID; autism; hyperactivity; MECP2; array CGH