15q11q13 microduplication syndrome (ORPHA:238446)
The 15q11-q13 microduplication (dup15q11-q13) syndrome is characterized by neurobehavioral disorders, hypotonia, cognitive deficit, language delay and seizures. Prevalence is unknown.
Epidemiology
To date, about 30 cases with syndrome of maternal origin have been reported.
Clinical description
The syndrome of maternal origin manifests in early childhood by developmental delay particularly in language, hypotonia, seizures often resistant, behavioral problems sometimes falling within the autism spectrum disorders (ASDs), and subtle or no dysmorphic features (macrocephaly, down-slanting palpebral fissures, epicanthal folds, expressionless face, clinodactyly, syndactyly) and short stature. A late-onset Lennox-Gastaut syndrome has been described. Cardiac defects have occasionally been reported. The clinical picture is highly variable even within the same family. Paternal duplications are rarely symptomatic (developmental delay/ behavioral disorders).
Etiology
The syndrome is due to interstitial duplications that encompass the imprinted Prader-Willi/Angelman critical region (PWACR), of which deletions lead to Prader-Willi and Angelman syndromes (see these terms). The chromosome 15q proximal region is unstable and rich in low-copy repeat (LCR) sequences that are often substrates of clinically relevant rearrangements with various parent-of-origin effects, including duplications that occur preferentially on the maternal chromosome. The causative genes are imprinted and expressed from the maternal allele. Only two maternally expressed genes, UBE3A and ATP10C, are located in the imprinted domain. Interstitial duplications are of an almost uniform 4 Mb size, sharing the same breakpoints with deletions, and about 2/3 of them appear to arise from an interchromosomal event, the remaining being intrachromosomal. Interstitial triplications have rarely been reported. Interstitial duplications occur usually de novo and are much less frequent than inverted duplications leading to the inv dup(15) syndrome (see this term).
Diagnostic methods
Diagnosis should be suspected in any child with early hypotonia, minor dysmorphic features, developmental delay/intellectual disability, ASD and seizures. Diagnosis is confirmed by standard cytogenetics (G-R-banding, able to identify most but not all duplications) and interphase fluorescence in situ hybridization (FISH) using probes from both proximal chromosome 15 and the PWACR, which shows the dup15q11-q13 encompassing the PWACR. Molecular studies (microsatellite analysis on parental DNA and methylation-specific PCR on proband DNA) are needed to detect the parent-of-origin. Comparative genomic hybridization microarray (aCGH) is a powerful method to detect the duplication extent.
Differential diagnosis
Differential diagnosis includes the other causes of developmental delay, ASD, and epilepsy. Severe early hypotonia may lead to genetic evaluation for PWS, showing the dup15q11-q13. Genetic testing rules out other disorders with a similar clinical picture and associated with supernumerary marker chromosome (SMC) derived from 15, such as inv dup(15) or, more rarely, double SMC resulting in partial hexasomy of the maternally inherited PWACR.
Antenatal diagnosis
Prenatal diagnosis is possible. Cells, obtained by choriocentesis or amniocentesis, can be analyzed by a combination of cytogenetic (G-R-banding, FISH), and molecular (methylation analysis) methods.
Genetic counseling
Genetic counseling should be cautious as the dup15q11-q13 syndrome is usually sporadic and rarely familial.
Management and treatment
The multidisciplinary management includes a comprehensive neurological and developmental evaluation. A video-EEG study is recommended to characterize the seizures and to determine the first choice pharmacotherapy. Regular follow-up is essential, as the seizures may be hard to control. Developmental evaluations allow planning early physical, occupational and speech interventions. Cardiac ultrasound should be performed in all carriers to exclude a cardiac defect.
Prognosis
Survival is not significantly reduced.

                            Last update: 
                            March 2011


                            - Expert reviewer(s): 
                            Dr Marie-France PORTNOI