Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

Abstract

WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome is a rare genomic disorder caused by deletion of the 11p14-p12 chromosome region. The majority of WAGR patients have mental retardation and behavioral problems, and more than 20% of the patients also have features of autism. While the Wilms tumor/genitourinary anomalies and aniridia are caused by deletion of WT1 and PAX6 respectively, the genomic cause of mental retardation and autism in WAGR syndrome remains unknown. Using oligonucleotide arrays, we have characterized the 11p14-p12 deletions in 31 patients and identified all the genes involved in each deletion. The deletions had sizes ranging from 4.9 to 23 Mb that encompass 18–62 genes (40 on average). In addition to WT1 and PAX6, all the patients had deletion of PRRG4 (transmembrane gamma-carboxyglutamic acid protein 4). The majority of them had deletion of BDNF (brain-derived neurotrophic factor) and SLC1A2 [solute carrier family 1 (glial high affinity glutamate transporter) member 2]. Deletion of BDNF and SLC1A2 occurred in patients with autism more frequently than in those without autism. Literature review on the functions of the genes suggests that haploinsufficiency of SLC1A2, PRRG4, and BDNF may contribute to mental retardation and behavioral problems. In particular, BDNF may modulate the risk of autism in WAGR patients as suggested by its link with Rett syndrome as a target of MECP2. We observed that all the de novo deletions occurred in the chromosome 11 inherited from the father in the families genotyped, implying a predisposition for de novo mutations occurring in spermatogenesis and possible involvement of imprinting in cognitive impairment in WAGR patients.

Aniridia

“…3,4 A variety of dysmorphic features and behavioural, neurological and metabolic abnormalities, including obesity, may also be present. 3,23,24 MOLECULAR AND GENETIC BASIS OF ANIRIDIA Loss of function of one copy of the PAX6 gene can be identified in about 90% of aniridia cases, with intragenic mutations accounting for two-thirds and chromosomal rearrangements for one-third of cases. 4,25 About two-thirds of all cases are familial and show dominant inheritance with very-high penetrance.…”

“…The phenotypic spectrum is determined by the identity of the genes in the deletion. 3,23,24 Reproductive transmission is thus significantly reduced. Larger WAGR deletions therefore generally arise de novo in each case, and siblings are unlikely to be affected, although rare cases of balanced translocations in a parent can lead to recurrent larger deletions.…”

Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling

“…In this study, we performed an extensive functional analysis of COM MD9, a COM MD family member that is frequently deleted in WAGR syndrome (MIM 194072), a congenital condition caused by a microdeletion and haploinsufficiency at 11p13 (Xu et al, 2008). We report that COM MD9 is incorporated into the CCC complex and plays a critical role in endosomal sorting of Notch family members.…”

Evaluation of Pax6 mutant rat as a model for autism

“…Human PAX6 gene is originally identified in chromosomal region 11p13 as one related with WAGR (Wilm's tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome [18,19], which is a rare genetic disorder caused by chromosomal deletion of the 11p12-p14 region. The majority of WAGR patients have mental retardation and behavioral problems, and importantly, more than 20% of the patients also have features of autism [20,21]. Recent studies have identified PAX6 mutations in individuals who manifest mental retardation, aniridia and autism [22][23][24].…”