Inverted duplicated chromosome 15 syndrome (ORPHA:3306)
A rare, complex chromosomal duplication/inversion in the region 15q11.2-q13.1 characterized by early central hypotonia, global developmental delay and intellectual deficit, autistic behavior, and seizures.
Epidemiology
Prevalence at birth is estimated at 1 in 30,000 but may be an underestimate. In patients with developmental concerns (developmental delay, intellectual disability, or autism spectrum disorder) or multiple congenital anomalies, the prevalence of partial tetrasomy of chromosome 15 is estimated to range between 1/253-584. There is an observed male predilection of 2:1.
Clinical description
Presentation is typically with neonatal hypotonia, feeding difficulties and gross motor delay. Global developmental delay is typical in early childhood with speech and language particularly affected. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. Most children and adults have moderate to severe intellectual disability. The distinct behavioral disorder manifesting in children and adolescents has been widely described as autistic or autistic-like. Seizures occur in over half of affected individuals, with onset typically between 6 months and 9 years, and may include infantile spasms and myoclonic, tonic-clonic, tonic, atonic, atypical absences, and focal seizures. Various EEG (electroencephalography) abnormalities have been described. Muscle hypotonia is observed in almost all individuals, associated, in most cases, with joint hyperextensibility and drooling. Facial dysmorphism is absent or subtle, and major malformations are rare.
Etiology
Chromosome region 15q11q13, known for its instability, is highly susceptible to clinically relevant genomic rearrangements, such as supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15 (Inv dup(15)). It results in tetrasomy 15p and partial tetrasomy 15q. Large rearrangements, containing the Prader-Willi/Angelman syndrome critical region (PWS/ASCR), are responsible for the inv dup(15)/isodicentric 15 (idic(15)) phenotype.
Diagnostic methods
Diagnosis is established by standard cytogenetic and FISH (fluorescence in situ hybridization) analysis, using probes both from proximal chromosome 15 and from the PWS/ASCR. Microsatellite analysis on parental DNA or methylation analysis on the proband DNA are also needed to detect the parent-of-origin of the inv dup(15) chromosome. Array CGH (comparative genomic hybridization) has been shown to be a powerful approach for identifying and detecting both the increases in copy number of the 15q11.2q13.1 region and its extent, as well as atypical forms of idic(15).
Differential diagnosis
The possible occurrence of double supernumerary isodicentric chromosomes derived from chromosome 15, resulting in partial hexasomy of the maternally inherited PWS/ASCR, should be considered in the differential diagnosis. Mitochondrial encephalomyopathy, Rett and Angelman syndromes, and CDKL5 mutations should also be considered in the differential diagnosis.
Antenatal diagnosis
Due to possible maternal germline mosaicism, antenatal diagnosis maybe considered where there is an affected sibling.
Genetic counseling
Genetic counseling may be proposed due to possible maternal germline mosaicism but large rearrangements involving the PWS/ASCR and idic(15) are nearly always sporadic.
Management and treatment
Management of inv dup(15)/idic(15) includes a comprehensive neurophysiologic and developmental evaluation.
Prognosis
Life expectancy is not significantly reduced. Many adults have a severe intellectual disability with poor social interaction, and are unable to manage full self-care. Most live at home with their original family and a minority in a sheltered environment.

                            Last update: 
                            June 2020


                            - Expert reviewer(s): 
                            Pr Agatino BATTAGLIA