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.