Duplication at Xq13.3-q21.1 with syndromic intellectual disability, a probable role for the ATRX gene.
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.
Unidad de Genética y Diagnostico Prenatal, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Francisco
F
Martínez
Mónica
M
Roselló
Sonia
S
Mayo
Sandra
S
Monfort
Silvestre
S
Oltra
Carmen
C
Orellana
D000293:Adolescent; D002648:Child; D041321:Chromosomes, Human, X; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D049951:X Chromosome Inactivation; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000235:genetics
D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
MECP2; XLID; array CGH; autism; hyperactivity