Paracentric inversion (PAI) is a common rearrangement that involves two breaks within the same chromosome arm, followed by the reinsertion of the chromosome segment into its original location after a 180° rotation. The incidence of PAIs in the general population has not been clearly established but seems to range from 0.1 to 0.5% [1,2]. Although PAIs are generally considered to be harmless with no phenotypic consequences, an abnormal phenotype has been described in cases where microduplications/microdeletions occur, or critical genes have been interrupted at the breakpoints [3-5].
Paracentric inversions can only be detected by conventional cytogenetic analysis. However, submicroscopic chromosomal imbalances at breakpoint junctions of the inverted segment can be unveiled using molecular cytogenetic techniques, such as array comparative genomic hybridization (aCGH).
In this report we present a novel
The patient is a 14-year-old boy with intellectual disability who was diagnosed prenatally with a paracentric inversion of the long arm of chromosome 20 (20q). Chorionic villus sampling was performed during the 12th week of gestation due to advanced maternal age (35 years old). The karyotype of the fetus was described as 46,XY,inv(20) (q13.1q13.3). Parental karyotypic analysis was not performed at that time.
At birth, his weight was 2900 g and he had an apparently normal phenotype. At 9 months of age, the parents noticed hypotonia, head support delay and inability to sit-up by the age of 9 months. At approximately 17 months of age, he presented with developmental delay, dysmorphic features, psychomotor retardation and Duane syndrome anomalies. Brain magnetic resonance imaging (MRI) revealed cerebellar hypoplasia. He began occupational therapy and speech therapy at 4 years of age.
Presently, he does not have complete control and coordination of his body, especially for delicate movements. He has normal physical and sexual development, but he has problems in perception, speech expression and in self-care, although he shows gradual improvement. The patient does not show evidence of autism, stereotypy and automatic repetition of vocalizations such as echolalia. He is a happy and sensitive child who often cries but easily becomes happy. He attends a special school, is social, cooperative, seeks friendships and likes playing with other children.
Cytogenetic analysis of the boy and his parents was performed on G-banded chromosome preparations at high resolution level (>550 bphs) from PHA (phytohemagglutinin)-stimulated peripheral blood lymphocytes. Imaging and karyotyping were achieved
Fluorescent
Molecular karyotyping was also performed in order to identify possible submicroscopic unbalanced chromosomal aberrations not detectable by G-banded chromosomal analysis. The G3 4x180k CGH+SNP (single nucleotide polymorphism) microarray platform with an average probe spacing of 13 kb (Agilent Technologies, Santa Clara, CA, USA) was used. Samples were processed according to manufacturer’s instructions and CytoGenomics 4.1 software (Agilent Technologies) was used for feature extraction and visualization of the resulting data. For annotation of genes in the deleted or duplicated genomic segments the University of California Santa Cruz (UCSC) Genome Browser (
Array comparative genome hybridization revealed a 100 kb microdeletion in the inverted segment at the 20q13.12 region, which is considered a copy number polymorphism. In addition, an interstitial deletion of 1.97 Mb at the chromosomal region 20q12 (20:38157428-40128669) was revealed, distal from the inverted segment that included 11 genes (Table 1), among which is the
Relevant array comparative genomic hybridization findings, genes content and characterization.
del 11q14.3-q21 (4.5 Mb) | 89545468 | 94077250 | uncertain clinical significance | |
del 20q12 (1.97 Mb) | 38157428 | 40128669 | uncertain clinical significance | |
del 20q13.12 (100 kb) | 43916414 | 44016199 | copy polymorphism number |
A novel PAI of the long arm of chromosome 20 [inv(20) (q13.1q13.3)] is described in a patient with mental retardation. To the best of our knowledge, this case is the first reported PAI of 20q in the literature. Although the great majority of PAIs are familial (about 90.0%) [7], conventional cytogenetic analysis of the patient’s parents revealed the
In general, PAIs are balanced and have no phenotypic consequences for the carriers. However, in cases where microdeletions/microduplications occur at the breakpoints, an abnormal phenotype could result [3-5]. In our patient, aCGH showed a 100 kb microdeletion in the inverted segment at the 20q13.12 region-considered polymorphic CNP (copy number polymorphism), since it is reported in the database of genomic variance (DGV) and has not been associated with abnormal phenotypic features in carriers. Two other microdeletions at chromosomal regions 20q12 and 11q14.3q21, which were also found in our patient, were investigated for genes that could have contributed to the proband’s phenotype.
Constitutional deletions concerning larger segments of the long arm of chromosome 20 are very rare, with only eight cases reported so far [8-13], containing genes that may be responsible for the development of the heart and the brain. The 20q12 (1.97 Mb) microdeletion found in our proband contains one important OMIM morbid gene,
The majority of 11q deletions are terminal and has been associated with a genetic disorder known as Jacobsen syndrome [16]. Interstitial 11q deletions are rare and only 35 cases have so far been described in the literature. They are highly heterogeneous in size and position and present with variable phenotypic characteristics, with most cases exhibiting mild to severe mental retardation, and as in our proband, developmental delay. However, in only six of the reported cases, the breakpoints of the deleted segment have been identified by molecular cytogenetic techniques [17,18], thus, it is hard to define the distinct genotype/ phenotype correlation of the 11q deletion. The common interstitial 11q deleted region contains the 4.5 Mb 11q14.3-11q21 microdeletion was also found in our proband [18]. The genes contained in the 11q14.3-11q21 microdeleted region in our proband are 36 and are characterized as genes with uncertain clinical significance. The most important one is
In conclusion, this is the first report of a patient with an apparently balanced
This case report describes a new chromosomal entity with an important contribution to the management of prenatal diagnosis with similar findings. Array comparative genome hybridization is proven to be a useful technique for detecting unbalanced submicroscopic rearrangements with the exception of balanced chromosomal rearrangements and mosaicism of less than 20.0%. It could be offered prenatally or postnatally, in combination with conventional cytogenetic techniques, especially in cases of