**8. Smith-Magenis and Potocki-Lupski syndromes**

Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are two prototypical genomic disorders caused by reciprocal deletion (SMS) or duplication (PTLS) resulting in gene copy number variation on chromosome 17. SMS results from a *de novo*, recurrent, 3.7 Mb deletion in 17p11.2 – del(17)(p11.2p11.2) in ~73% of cases, that is a consequence of NAHR mediated by LCRs flanking the region [77-79]. However, many of the pleiotropic fea‐ tures of SMS appear to result from haploinsufficiency of a single gene lying in the middle of the SMS critical region, *retinoic acid induced 1* (*RAI1),* as determined by the identification of non-deletion SMS patients with heterozygous point mutations in *RAI1* [80-82]. Patients with mutations in *RAI1* manifest most of the phenotypes observed in subjects with a chromoso‐ mal SMS deletion, demonstrating that the reduced dosage of the *RAI1* gene alone may cause much of the SMS phenotype [81, 83].

Both SMS and PTLS manifest a broad range of opposing or overlapping phenotypes. SMS is characterized by multiple congenital anomalies, including otolaryngologic, ophthalmologic, brain, cardiac, craniofacial, and renal abnormalities, as well as intellectual disability (ID), brachydactyly, sleep disturbance, hearing impairment, obesity, scoliosis, and other neurobe‐ havioral abnormalities [84, 85]. Specifically, SMS patients display aggressive and self-injuri‐ ous behaviour, including polyembolokoilamania [84], as well as characteristic repetitive behaviors, including autoamppexation or "self-hugging," which is an identifying feature of the disorder [86, 87]. More recently, SMS patients have also been described as meeting the criteria for autism spectrum disorder (ASD) [88].

communication. However, no defects in olfactory communication or function were observed in these mice. Restricted behaviors and inflexibility were evaluated with a battery of behav‐ ioral tests, including the Morris water maze and the Barnes maze. These tests revealed that patDp/+ mice do not respond as flexibly to a change in situation as wild-type or matDp/+ mice. No overt defects in learning and memory were observed in either the patDp/+ or matDp/+ mice by the Morris water maze or conditioned fear test, although patDp/+ mice did display generalized fear and elevated anxiety-like behavior. The abnormal neurobehavioral phenotypes observed in this CNV-based model of ASD could not be attributed to gross mor‐ phological or histological changes in the olfactory bulb, cerebral cortex, hippocampus, amygdala, corpus callosum, or cerebellum. Nor were any abnormalities in the number of Purkinje cells detected in the cerebellum, suggesting that the underlying pathomechanism responsible for these phenotypes is likely due to aberrations in molecular pathways that re‐

The gene *Ube3a* (also known as E6-AP) codes for E3 ubiquitin-protein ligase, which belongs to a family of E3 ligase genes that are involved in synaptogenesis and have recently been linked to the pathogenesis of ASD [62]. Given the known association of the gene *UBE3A* with AS and its maternal-specific expression pattern in neurons, a mouse model that overex‐ presses this gene was generated to test the hypothesis that *Ube3a* is responsible for many of the phenotypes associated with duplication of 15q11-13 [62]. Transgenic overexpression of *Ube3a* via bacterial artificial chromosome (BAC) recombineering in mice resulted in autisticlike neurobehavioral phenotypes, including defects in communication, abnormal social be‐ havior, and increased repetitive or stereotypic behavior [62]. Similar to the phenomenon observed in human patients, these effects were also determined to be dosage-sensitive, as the phenotypes were more penetrant in mice with three-fold overexpression of *Ube3a* than in those observed in mice with two-fold overexpression of this gene. Furthermore, it was de‐ termined that glutamatergic synaptic transmission was suppressed, providing a potential

Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are two prototypical genomic disorders caused by reciprocal deletion (SMS) or duplication (PTLS) resulting in gene copy number variation on chromosome 17. SMS results from a *de novo*, recurrent, 3.7 Mb deletion in 17p11.2 – del(17)(p11.2p11.2) in ~73% of cases, that is a consequence of NAHR mediated by LCRs flanking the region [77-79]. However, many of the pleiotropic fea‐ tures of SMS appear to result from haploinsufficiency of a single gene lying in the middle of the SMS critical region, *retinoic acid induced 1* (*RAI1),* as determined by the identification of non-deletion SMS patients with heterozygous point mutations in *RAI1* [80-82]. Patients with mutations in *RAI1* manifest most of the phenotypes observed in subjects with a chromoso‐ mal SMS deletion, demonstrating that the reduced dosage of the *RAI1* gene alone may cause

main to be determined.

260 Recent Advances in Autism Spectrum Disorders - Volume I

mechanism underlying the neurobehavioral phenotypes.

much of the SMS phenotype [81, 83].

**8. Smith-Magenis and Potocki-Lupski syndromes**

The PTLS duplication was the first predicted reciprocal duplication to be described [89]. PTLS was identified and initially defined much later than SMS, ([89] versus Smith et al. 1986); as a result, fewer PTLS patients have been medically examined and fewer studies of the clinical phenotypes are available in the literature. The clinical features that have been ob‐ served in patients with PTLS are distinct from those seen in SMS [15], although cognitive and neurobehavioral abnormalities are present in both disorders. PTLS patients lack the self-injurious behaviors, abnormal facies, and sleep disturbance, as well as some of the con‐ genital anomalies found in most individuals with SMS. The features observed in greater than 90% of PTLS patients are developmental delay, neurobehavioral abnormalities, lan‐ guage impairment, cognitive impairment, poor feeding, hypotonia, and oropharyngeal dys‐ phasia [15, 90]. When evaluated by objective clinical assessment, the majority of PTLS patients have autistic features such as decreased eye contact, atypicality, withdrawal, anxi‐ ety, and inattention, meeting criteria for a diagnosis of autistic spectrum disorder (ASD) or pervasive developmental disorder not otherwise specified, and making ASD the most com‐ mon and consistent feature observed in PTLS. [14].

Most PTLS patients have no distinctive facial abnormalities but they can have a triangularshaped face. The other clinical features present in over half of patients include sleep apnea, abnormal EEG, attention deficit, hypermetropia, and cardiovascular abnormalities [15]. These cardiovascular abnormalities can typically include both structural and conduction de‐ fects, such as atrial or ventricular septal defects, bicuspid aortic valve, dilated aortic root, di‐ lation of the pulmonary annulus, patent foramen ovale, or hypoplastic left heart [15, 91-93].

Upon molecular analysis, most [22 of 35] PTLS patients included in the first multidisci‐ plinary study were determined to carry a common recurrent 3.7 Mb duplication in 17p11.2 mediated by the same proximal and distal SMS-REPs which also mediate the re‐ ciprocal common recurrent SMS deletion [15]. Others have uncommon and sometimes complex genomic rearrangements, all of which involve duplication in 17p11.2 [94]. The smallest PTLS duplication identified to date occurred in a single patient and is 1.3 Mb in size. This duplicated segment contains 14 genes, including both *RAI1,* the major contribu‐ ting gene for the reciprocal deletion causing SMS, as well as the steroid-metabolism reg‐ ulating gene, *SREBP1*. This patient demonstrates all typical PTLS phenotypes [94]. Whether, or to what extent, PTLS results from *RAI1* gene over-dosage still remains to be elucidated, although mouse studies (described below) have shown that it is likely re‐ sponsible for at least some of the symptoms [95].
