Potocki-Lupski Syndrome

A number sign (#) is used with this entry because the Potocki-Lupski syndrome (PTLS) is a contiguous gene syndrome caused by duplication of chromosome 17p11.2.

See also Smith-Magenis syndrome (SMS; 182290), which is associated with the reciprocal deletion of chromosome 17p11.2 and shows overlapping clinical features.

Description

Potocki-Lupski syndrome is a developmental disorder characterized by hypotonia, failure to thrive, mental retardation, pervasive developmental disorders, and congenital anomalies. All reported cases have occurred sporadically without bias in the parental origin of rearrangements. Most duplications are 3.7 Mb in size and only identifiable by array comparative genomic hybridization (CGH) analysis. Approximately 60% of PTLS patients harbor a microduplication of chromosome 17p11.2 reciprocal to the common recurrent 3.7-Mb microdeletion in SMS (summary by Shchelochkov et al., 2010).

Clinical Features

Brown et al. (1996) described 2 unrelated males with developmental delay and mild dysmorphic facial features associated with duplication of 17p11.2. The extent of the duplicated region was determined using single-copy DNA probes and was confirmed by fluorescence in situ hybridization. Brown et al. (1996) raised the question of whether this was a reciprocal of the Smith-Magenis syndrome deletion.

Potocki et al. (2000) reported 7 unrelated patients evaluated for developmental delay who had de novo duplications of the same region deleted in SMS. Clinical features included mild mental retardation, behavioral abnormalities such as attention-deficit, hyperactivity, and autism, short stature, and dental abnormalities such as malocclusion and crowded teeth. Two patients had dysmorphic facies with triangular facies, smooth philtrum, high-arched palate, frontal bossing, and mandibular and maxillary hypoplasia. A third patient had a submucous cleft palate and bifid uvula. In general, however, the phenotype was less severe than that seen in SMS deletion syndrome.

Potocki et al. (2007) performed systematic multidisciplinary clinical evaluations in a subset of 10 subjects, including 1 subject who harbored the smallest duplication identified to that time. Apart from developmental delay, language impairment, and cognitive impairment, the most frequent clinical features of PTLS were hypotonia, poor feeding and failure to thrive in infancy, oral-pharyngeal dysphagia, autistic features, obstructive and central sleep apnea, structural cardiovascular abnormalities, electroencephalogram (EEG) abnormalities, and hypermetropia. Features reported in more than 50% of patients with the reciprocal SMS deletion were not observed or were seen only infrequently in the duplication 17p11.2 syndrome, including short stature, hearing impairment, otolaryngologic abnormalities, ophthalmic abnormalities such as myopia and iris hamartomata, genitourinary and/or renal anomalies, clinically significant scoliosis, and hypercholesterolemia. Potocki et al. (2007) suggested that the vast majority of PTLS patients showed features of autistic spectrum disorder.

Greco et al. (2008) reported 3 girls with PTLS and de novo duplication of chromosome 17p11.2. Clinical features included neonatal hypotonia, failure to thrive, and severe language delay. There were variable dysmorphic features, including triangular face, microcephaly, trigonocephaly, hypertelorism, and flat philtrum. Common features included wide nasal bridge, epicanthal folds, strabismus, large mouth, wide third phalanges on the hands, and increased gap between the first and second toes. Cognitive testing showed severe, moderate, and mild mental retardation, respectively. In contrast to the findings of Potocki et al. (2007), none of the 3 girls had features of autism by several specific diagnostic scales.

Cytogenetics

Using pulsed field gel electrophoresis (PFGE), Potocki et al. (2000) identified a unique junction fragment, of the same apparent size, in each patient with multiple congenital anomalies and mental retardation examined by them. Further molecular analyses suggested that the de novo 17p11.2 duplication was preferentially paternal in origin, arose from unequal crossing-over due to homologous recombination between flanking repeat gene clusters, and probably represents the reciprocal recombination product of the SMS deletion.

Potocki et al. (2007) reported the molecular assays of 35 subjects with dup(17)(p11.2p11.2). Of these subjects, 22 harbored a 'common' duplication (approximately 3.7 Mb), and 13 harbored nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb, as determined by multiple independent molecular assays.

Zhang et al. (2010) identified an uncommon recurrent 5-Mb duplication at chromosome 17p11.2 in 2 (2.7%) of 74 patients with PTLS, including 35 of whom had not been characterized at the molecular level. This duplication was the reciprocal of an uncommon 5-Mb deletion found in SMS patients (Shaw et al., 2004). The duplicated region encompassed the entire common 3.7-Mb duplication, and the PTLS patients did not show additional clinical features. Further analysis showed that the duplications shared the same recombination hotspot with the reciprocal SMS-associated deletion, and occurred in proximity to a recently delineated allelic homologous recombination (AHR) hotspot-associated sequence motif. Among the remaining uncharacterized PTLS patients studied by Zhang et al. (2010), 25 had the common 3.7-Mb duplication, and 8 had nonrecurrent duplications with continuous copy number gain ranging in size from 0.41 to 13.3 Mb. Four (50%) of the 8 nonrecurrent duplications had complex 17p rearrangements associated with replication-based mechanisms. Together with previously reported PTLS duplications representing a total of 74 cases, Zhang et al. (2010) concluded that 50 (67.6%) have common recurrent duplications, 2 (2.7%) have uncommon recurrent duplications, and 22 (29.7%) have nonrecurrent duplications. Thus, approximately 70% of PTLS duplications are recurrent and occur by the NAHR mechanism. The smallest region of overlap was reduced to 125 kb on chromosome 17p11.2, which included the RAI1 gene (607642), suggesting that this gene is mainly responsible for the phenotype.

Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 17p11.2 duplication was identified in 15 cases and no controls for a p value of 0.0008 and a frequency of 1 in 1,050 cases.

Diagnosis

Potocki et al. (2000) initially hypothesized that patients with 17p11.2 duplication did not come to medical attention because of their milder phenotype. However, the findings of Potocki et al. (2007) revealed that these patients may have substantial medical illness as well as neurobehavioral abnormalities that, except for the developmental delay, may go unrecognized until later infancy or childhood. Potocki et al. (2007) suggested that most patients likely elude an etiologic diagnosis because of the limitations of conventional cytogenetic analyses.

Pathogenesis

Nonallelic homologous recombination between region-specific low-copy repeats (LCRs) (also known as 'segmental duplications') is a major cause of DNA rearrangements associated with many genomic disorders (Stankiewicz and Lupski, 2002). The proximal short arm of chromosome 17 is particularly rich in LCRs and is a regional locus for 4 genomic disorders: Charcot-Marie-Tooth type 1A (CMT1A; 118220); hereditary neuropathy with liability to pressure palsies (HNPP; 162500); Smith-Magenis syndrome (182290); and the 17p11.2 duplication syndrome (Potocki et al., 2007).

Shaw et al. (2002) analyzed the haplotypes of 14 families of patients with SMS and 6 families of patients with duplication of the same region using microsatellite markers directly flanking the SMS common deletion breakpoints. The data indicated that the deletion and its reciprocal duplication of chromosome 17p11.2 result from unequal meiotic crossovers mediated through nonallelic homologous recombination (NAHR) that occurs via both interchromosomal and intrachromosomal exchange events between the proximal and distal SMS repeats. There appeared to be no parental-origin bias associated with common SMS deletions and the reciprocal duplications.

Bi et al. (2003) reported a recombination hotspot associated with both the common SMS deletion and the reciprocal duplication, dup(17)(p11.2p11.2), demonstrating the reciprocity of the crossover events as had been demonstrated for HNPP and CMT1A.

Liu et al. (2011) assembled 2 patient cohorts with reciprocal genomic disorders, deletion-associated Smith-Magenis syndrome and duplication-associated Potocki-Lupski syndrome. By assessing the full spectrum of rearrangement types from the 2 cohorts, Liu et al. (2011) found that complex rearrangements (those with more than 1 breakpoint) are more prevalent in copy-number gains (17.7%) than in copy-number losses (2.3%), an observation that supports a role for replicative mechanisms in complex rearrangement formation. Interestingly, for nonallelic homologous recombination-mediated recurrent rearrangements, Liu et al. (2011) showed that crossover frequency is positively associated with the flanking low-copy repeat (LCR) length and inversely influenced by the inter-LCR distance. To explain this, they proposed that the probability of ectopic chromosome synapsis increases with increased LCR length, and that ectopic synapsis is a necessary precursor to ectopic crossing-over.

Nomenclature

Potocki-Lupski syndrome was the first predicted reciprocal microduplication syndrome described, being the homologous recombination reciprocal of the Smith-Magenis syndrome microdeletion del(17)(p11.2p11.2). Because the cytogenetic nomenclature can be cumbersome when used to refer to affected individuals, Potocki et al. (2007) proposed that the 17p11.2 microduplication syndrome be referred to by the eponym 'Potocki-Lupski syndrome' (PTLS).

Animal Model

Mice with a heterozygous duplication, Dp(11)17, of the region on mouse chromosome 11 that is syntenic to human chromosome 17 are underweight and show behavioral anomalies such as impaired contextual fear conditioning (Walz et al. (2003, 2004)). Walz et al. (2006) generated compound heterozygous mice with a Dp(11)17 allele and a null Rai1 (607642) allele, thus resulting in normal disomic gene dosage of Rai1. Normal Rai1 dosage rescued many of the phenotypes observed in heterozygous Dp(11)17 mice, including normalization of body weight and partial normalization of behavior. The phenotype was rescued despite altered trisomic copy number of the other 18 or so genes in the region. Walz et al. (2006) concluded that duplication of Rai1 is responsible for decreased body weight in Dp(11)17 mice and that Rai1 is a dosage-sensitive gene involved in body weight control and complex behavioral responses.

Molina et al. (2008) found that the PTLS mouse model, Dp(11)17/+, recapitulated some of the physical and neurobehavioral phenotypes present in patients. Dp(11)17/+ male mice displayed normal home-cage behavior, with the exception of decreased vocalization during handling and decreased nesting behavior compared to wildtype mice. Dp(11)17/+ mice also showed increased anxiety, increased dominant behavior in specific tests, a subtle impairment in the preference for a social target versus an inanimate target, and an impaired response to social novelty. These behaviors were interpreted as representing autistic features in humans. Dp(11)17/+ mice had lower body weight and lower brain weight at 3 months of age compared to wildtype, although the percentage of brain weight to total weight was higher in the transgenic mice. Gene expression array analysis and PCR studies showed overexpression of several genes, including Rai1, in the hippocampus of transgenic mice. The data also showed that candidate genes influencing behavior included not only most of the duplicated genes, but also normal-copy genes that flanked the engineered interval.