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Duplication at Xq13.3–q21.1 with syndromic intellectual disability, a probable role for the ATRX gene
Author(s) -
Martínez Francisco,
Roselló Mónica,
Mayo Sonia,
Monfort Sandra,
Oltra Silvestre,
Orellana Carmen
Publication year - 2014
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36371
Subject(s) - atrx , gene duplication , genetics , microcephaly , gene , fragile x syndrome , intellectual disability , biology , mecp2 , point mutation , hypotonia , mutation , phenotype
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 6 Mb 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. © 2014 Wiley Periodicals, Inc.