Original articleRelationship between clinical and genetic features in “inverted duplicated chromosome 15” patients
Introduction
Recent advances in cytogenetics and molecular genetics have renewed interest in the study of chromosomal abnormalities, such as subtle chromosomal rearrangements, and marker chromosomes (small accessory chromosomes) as a possible cause for behavioral disturbances and mental retardation [1], [2], [3], [4]. Among the supernumerary marker chromosomes, inverted duplicated chromosome 15 (Inv dup[15]) represents a group of particular interest because of their frequency within the population (0.4/1000) and the involvement of a gene-rich region [5], [6], [7], [8], [9].
The proposed mechanism for its formation is a U-type exchange between nonsister chromatids [10], [11], and the size of the 15 regions involved in the tetrasomy is correlated with the breakpoint of rearrangement. Two regions have been identified that are prone to breakage: one region is more proximal to the 15 centromere, which produces small Inv dup(15), and the other is more distal, which creates larger Inv dup(15) [12], [13]. Deletion of this chromosome region correlates with two other syndromes, namely Prader-Willi syndrome (PWS) and Angelman syndrome (AS) in which, among other symptoms, mental retardation is associated with behavioral disorders.
In the literature the importance of PWS/AS gene dosage has been related to the clinical severity of the phenotype [7], [10], [14], [15], [16], [17]. On the contrary, the correlation with the genic content of the marker and the clinical spectrum of Inv dup(15) syndrome is variable and is still a much-debated issue [6], [7], [9], [10], [12], [14], [15]. The clinical spectrum exhibited by subjects with Inv dup(15) includes muscle hypotonia, motor clumsiness, mild dysmorphisms, epileptic seizures, and cognitive deficits of varying severity that are always associated with severe behavioral disorders, such as distorted communication skills, poor social interaction, and stereotyped behavior. According to the DSM-IV diagnostic criteria [18], these behavioral disorders can be classified as pervasive developmental disorders (PDDs).
PDDs comprise autistic disorder, childhood disintegrative disorder, Rett syndrome, Asperger’s disorder, and also the large group of “PDDs not otherwise specified” that includes cases with atypical symptomatology: subthreshold behavioral manifestations, various neurologic symptoms, or severe-profound mental retardation.
In this study, six patients with Inv dup(15) were monitored, focusing on their neurologic and psychopathologic features, which until now have been only scantily investigated, with the aim to study the behavioral phenotype of the syndrome and identify a possible correlation between the clinical pattern and the genetic one.
Section snippets
Methods
All inpatients with mental retardation and behavioral disorders in the Child Neuropsychiatry Units of Bosisio, Brescia, and Varese General Hospitals usually undergo a karyotype analysis from peripheral blood lymphocytes using the standard technique. During 1995-1998, six patients (one male and five females between 4 and 14 years of age, mean age of 8.83 years) with a diagnosis of Inv dup(15) syndrome were observed.
Results
Genetic analysis revealed the maternal origin of Inv dup(15) in all six patients. In one patient a marker chromosome of paternal origin was suspected at cytogenetic heteromorphism investigations; subsequently, the maternal derivation of the marker was demonstrated by molecular techniques. All our patients displayed the large type of Inv dup(15) correlated with breakage at the distal breakpoint of rearrangement (Fig 1).
The general and neurologic features of the patients examined reflect the
Discussion
All the study patients presented a pathologic phenotype characterized by motor retardation, language delay, facial dysmorphisms, hypotonia, ataxia and/or dyspraxia, mild-to-severe cognitive deficit, and psychopathologic impairment always classifiable as PDD. The same neurologic signs, mental retardation, and autisticlike behavior have been described in almost all patients reported in other studies [7], [8], [9], [14], [16], [17], [23], [24].
The study patients also demonstrated highly varied
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