Cognitive and Behavioral Characterization of the Potocki-Lupski Syndrome (Duplication 17p11.2)
ABSTRACT To describe the cognitive and behavioral phenotypic features of the Potocki-Lupski syndrome (duplication 17p11.2), a recently recognized syndrome with multiple congenital anomalies and developmental delays.
Fifteen subjects were enrolled in an extensive multidisciplinary clinical protocol. Cognitive and behavior evaluations included a parent-report medical and psychological history form, intellectual assessment and assessments of adaptive behavior, executive functioning, and maladaptive behavior and emotions. Eight of the families completed an Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic.
The majority of patients (13 of 15) presented with intellectual disability. Moreover, the majority of patients also had moderate to severe behavioral difficulties, including atypicality, withdrawal, anxiety, and inattention. Many patients characterized also presented with autistic symptom pictures, some of whom (10 of 15) met diagnostic criteria for an autistic spectrum disorder, namely autistic disorder or pervasive developmental disorder not otherwise specified.
This work expands on the behavioral phenotype of duplication 17p11.2 (Potocki-Lupski syndrome). Further phenotypic analysis will aid in clinical diagnosis, counseling, and management of this newly characterized microduplication syndrome. The association between this syndrome and autistic spectrum disorder may contribute to further understanding the etiology of the pervasive developmental disorders.
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- "We presented here a case of PTLS which, both behaviorally and in terms of the specifics of his brain functioning , does not fit the categorization of ASD and permits the formulation of the hypothesis that the central feature of PTLS is in language (not social) dysfunction. Although it has been reported that 80% of PTLS patients show some autistic features  , there are reports of individuals with PTLS who demonstrate none of these features  . "
ABSTRACT: Potocki-Lupski syndrome (PTLS; OMIM 610883) is a genomic syndrome that arises as a result of a duplication of 17p11.2. Although numerous cases of individuals with PTLS have been presented in the literature, its behavioral characterization is still ambiguous. We present a male child with a de novo dup(17)(p11.2p11.2) and he does not possess any autistic features, but is characterized by severe speech and language impairment. In the context of the analyses of this patient and other cases of PTLS, we argue that the central feature of the syndrome appears to be related to diminished speech and language capacity, rather than the specific social deficits central to autism.Brain & development 12/2011; 34(8):700-3. DOI:10.1016/j.braindev.2011.11.003 · 1.54 Impact Factor
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ABSTRACT: Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.The American Journal of Human Genetics 02/2010; 86(3):462-70. DOI:10.1016/j.ajhg.2010.02.001 · 10.99 Impact Factor
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ABSTRACT: Smith-Magenis Syndrome is a contiguous gene syndrome in which the dosage sensitive gene has been identified: the Retinoic Acid Induced 1 (RAI1). Little is known about the function of human RAI1. We generated the full-length cDNA of the wild type protein and five mutated forms: RAI1-HA 2687delC, RAI1-HA 3103delC, RAI1 R960X, RAI1-HA Q1562R, and RAI1-HA S1808N. Four of them have been previously associated with SMS clinical phenotype. Molecular weight, subcellular localization and transcription factor activity of the wild type and mutant forms were studied by western blot, immunofluorescence and luciferase assays respectively. The wild type protein and the two missense mutations presented a higher molecular weight than expected, localized to the nucleus and activated transcription of a reporter gene. The frameshift mutations generated a truncated polypeptide with transcription factor activity but abnormal subcellular localization, and the same was true for the 1-960aa N-terminal half of RAI1. Two different C-terminal halves of the RAI1 protein (1038aa-end and 1229aa-end) were able to localize into the nucleus but had no transactivation activity. Our results indicate that transcription factor activity and subcellular localization signals reside in two separate domains of the protein and both are essential for the correct functionality of RAI1. The pathogenic outcome of some of the mutated forms can be explained by the dissociation of these two domains.BMC Molecular Biology 08/2010; 11:63. DOI:10.1186/1471-2199-11-63 · 2.06 Impact Factor