Duplication at Xq13.3-q21.1 with syndromic intellectual disability, a probable role for the ATRX gene.

[alpha-thalassemia]

Here we report on two unrelated male patients with syndromic intellectual disability (ID ) due to duplication at Xq 13 .3 -q 21 .1 , a region of about 6 â€‰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 MECP 2 , 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 can not 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 MECP 2 duplication .

Diseases
Validation

Diseases presenting "loss-of-function mutations" symptom

achondroplasia

alpha-thalassemia

aromatase deficiency

child syndrome

cowden syndrome

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erythropoietic protoporphyria

esophageal adenocarcinoma

familial hypocalciuric hypercalcemia

harlequin ichthyosis

hirschsprung disease

kallmann syndrome

kindler syndrome

lamellar ichthyosis

neonatal adrenoleukodystrophy

pendred syndrome

werner syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated