MICRODUPLICATION 22q11.2: A DESCRIPTION OF THE CLINICAL, DEVELOPMENTAL AND BEHAVIORAL CHARACTERISTICS DURING CHILDHOOD

Summary: Micriniuplication 22qU.2: a description of the clinical, developmental and behavioral characteristics during childhood: Microduplication 22q I i .2 is a recently discovered genomic disorder. So far. targeted research on the cognitive and behavioral characteristics of individuals with this niicroduplication is limited. Therefore, ? Flemish children (3-13 years old) with a microduplication 22ql 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their generai intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.l 1.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip. feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype. Key-words: 22?, 1 1.2 microduplication - Chromosome 22 - Mental retardation - Developmental delay - Behavioral problems. INTRODUCTION During the last decade, several patients with a microduplication 22q 1 1 .2 were identified. Edelman et ai (6) reported the first time on this new chromosomal syndrome. At present, there are about fifty unrelated cases known in literature, but this number continues to increase ( 1 7). The chromosomal structure in the region 22qll.2 is known to predispose to the occurrence of this imbalance, as well as its reciprocal deletion. Several low copy repeats with a highly homologous sequence are present, at fixed distances, in this chromosomal region. This can result in an unequal crossing-over between two homologues chromosomes. As a result, not only is this a recurrent imbalance, but the size of the duplication is the same in most cases (5). In case of the microduplication 22ql 1 .2 syndrome, the standard size is 3Mb, although there were also cases reported with duplications of 1Mb, 1.5Mb, 4Mb and 6Mb (16, 17). This 3Mb region is also the typically region that is deleted in the complementary genomic disorder, the 22q 1 1 .2 deletion syndrome, better known as DiGeorge/velocardiofacial syndrome (DGS/VCFS) (14). A recent large-scale case control association study confirmed that there is a link between this duplication and developmental disorders. The incidence in 15767 persons with a wide range of developmental problems (0.31%) was significantly higher (p=1.26xl0~5) than that of a control group of 8329 normal persons (0.06%) (E. Eichler, unpublished data, May 201 1). The clinical phenotype of children with this microduplication is mostly mild but has a very heterogeneous expression. There seems to be a considerable overlap with the phenotype of the deletion syndromes, although this might be the result of ascertainment bias (6). The phenotype is generally characterized by cognitive deficits, behavioral problems and mild dysmorphic features, like a high forehead, a broad nasal bridge and down-slanting palpebral fissures. Other major reported symptoms of microduplication 22ql 1 .2 are cardiovascular anomalies, speech delay, hearing loss, growth delay and psychiatric disorders like Attention Deficit Hyperactivity Disorder (ADHD), autism spectrum disorders or aggressive behavior. Moreover, a significant group of the patients seems to have an apparently normal phenotype, which hinders the diagnosis. …