Interstitial Tandem Duplication Research Articles

Duplication of the 15q11-q13 region: Clinical and genetic study of 30 new cases

Background15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1–BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism. MethodsRetrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region. ResultsFifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader–Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1–BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.

Familial trisomy 6p in mother and daughter

Several patients with partial trisomy 6p resulting from parental balanced translocations or from a de novo duplication or insertion have already been described. Here, we report on the first case of familial pure trisomy 6p as a result of interstitial tandem duplication. The patient, an 11-year-old female, presented with mild dysmorphic features, moderate intellectual disability with behavioral disturbances, immunodeficiency, and epilepsy. Conventional cytogenetic analysis showed a duplication of the 6p region in the patient and in her mother presenting with a partially overlapping phenotype. The rearrangement was confirmed and defined by molecular cytogenetic analysis, including FISH and array CGH analysis showing a gain of ~13.8 Mb from 6p12.3 to 6p21.31. The phenotype of a pure partial trisomy 6p is extremely heterogeneous depending on the gene contents of the duplicated region. The clinical features of our patients have been compared with overlapping cases from the literature.

A Xq21.31 duplication without features of Prader–Willi syndrome

We read with great interest the recent contribution by Pramyothin et al. [1], in Endocrine. They reported a 20-year-old man diagnosed with 47, XXY during childhood, who presents an appearance similar to that of Prader– Willi syndrome (PWS) with hypogonadism and gynecomastia, developmental delay, and short stature and obesity. Array-based comparative genome hybridization revealed duplication at Xq21.31 in addition to his abnormal karyotype. This duplication was also found in his mother who appeared normal. The authors hypothesized that the phenotype in this patient is a combination of both extra X chromosome and Xq21 duplication. On the other hand, Gabbertt et al. [2] have reported a 4-year-old male with an interstitial tandem duplication of Xq21.1–q21.31, maternally inherited, who presented with clinical features of PWS, and they conclude that duplication of chromosome Xq should be considered in the differential diagnosis of PWS, especially in males. In this sense, we have been evaluating a 3-year-old (at first time) male with developmental delay, autism, hyperactive behavior, hand stereotypes, large ears, synophrys, excessive hair in back, pes planus/valgus, and body mass index in the 95th percentile (height in 50th percentile and weight in 75th percentile), and without features of PWS. No contributory family history (and non-consanguineous parents), normal pregnancy, and delivery. Previous studies were negative for the findings in brain MRI, karyotype, and fragile X syndrome. 7q11.23, 17p13, 22q11.2, and 22q13.3 microdeletions were tested (FISH) and were negative. Recently, he was diagnosed at the age of 9 years of Xq21.31 duplication (3.9 Mb) by means of Cytogenetics Whole-Genomics 2.7 M array (Affymetrix): ArraysSNPs. In his mother, this genetic study was normal. We hypothesized that the duplication of chromosome Xq21.31 should be considered also in males with the association of developmental delay, autism, and hyperactive behaviour without phenotypic features of PWS. This association may be related with that at least seven loci of mental retardation syndromes encompassing the duplication in the Xq21.31 region [1].

Immunodeficiency in a child with partial trisomy 6p

We present a mentally retarded boy with partial trisomy of the short arm of chromosome 6 as a result of an interstitial tandem duplication of 6p12.2-p21.31 and immunodeficiency. Patients with mental retardation because of a chromosomal disorder or eponymous syndrome often experience recurrent respiratory tract infections as a result of their associated anatomical or neurological abnormalities. However, associated immune defects may also significantly contribute to their susceptibility to infections. Timely recognition and appropriate treatment of their immunodeficiency will greatly improve quality of life in these patients. Immunodeficiency may be the direct cause of recurrent respiratory tract infections in patients with mental retardation because of a chromosomal disorder or eponymous syndrome, even in the face of feeding difficulties and multiple episodes of aspiration, as is illustrated in this boy with partial trisomy 6p.

Molecular cytogenetic characterization of an inherited maternal duplication 20p11.21p13 associated with a small 20p11.21 deletion

Partial trisomy for the short arm of chromosome 20 is a relatively rare chromosomal abnormality. Most cases are derived from reciprocal translocations with the presence of partial monosomy of other chromosomes, and thus it has been difficult to delineate a specific phenotype [review in Chaabouni et al., 2007]. The molecular cytogenetic characterization of chromosome 20p rearrangements has been described in a few cases, which has allowed not only a more accurate genotype–phenotype correlation, but also the investigation of its underlying mechanisms. Sidwell et al. [2000] reported on a case of pure trisomy 20p arisen from de novo isochromosome formation, and associated with a non-reciprocal rearrangement involving the translocation of 20q11.1qter sequences onto chromosome 4p. Ravel et al. [2003] described a de novo isolated interstitial tandem duplication of chromosome 20p12 with no evidence of repeated sequences mediating this rearrangement. Ardalan et al. [2005] reported on a derivative with 20pter duplication and 20qter deletion originated from a familial pericentric intrachromosomal insertion following homologous pairing and crossover at meiosis. Chaabouni et al. [2007] described a case of de novo duplication spanning almost the whole short arm of chromosome 20p and associated with a small distal 20q deletion. Recently, Leclercq et al. [2009] reported on the first case of inversion duplication deletion involving the short arm of chromosome 20p (inv dup del 20p), which likely formed through a U-type exchange. High-resolution oligonucleotide CGH array revealed an 18.16 Mb duplication of 20p11.22p13 in association with a 20p13 terminal deletion sizing 2.02 Mb. Herein, we report on a case of trisomy 20p of maternal origin initially detected by conventional cytogenetic investigation. Molecular cytogenetic studies with fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) array revealed a direct tandem duplication of 20p11.21p13 associated with a contiguous 20p11.21 proximal microdeletion. The clinically normal mother had the same chromosome abnormality detected in about 15% of her lymphocyte cells. We have compared the phenotype of our patient to similar cases from the literature in order to further delineate trisomy 20p syndrome. The patient, a 21-year-old woman (Fig. 1), was the first child of non-consanguineous normal parents, aged 23 (mother) and 22 years (father). The mother had two miscarriages at 10 weeks of gestation and a normal son was subsequently delivered. Patient’s pregnancy was uncomplicated and she was delivered at term by caesarean. Apgar scores were 6 and 8 at 1 and 5 min, respectively. Birth weight was 2,960 g ( 10th centile) and birth length 49 cm (25th centile). The sucking reflex was present. At 2 months she had surgery for bilateral inguinal and umbilical hernia. By the age of 9 months she had little control over her head and neck and could not sit without support. She started walking at the age of 18 months with frequent falls. Independent walk was achieved at 2 years of age. On examination at 21 years of age, occipital-frontal circumference (OFC) was 54 cm (2–50th centile), height 1.70 m (90th centile) and weight 65 kg (75–90th centile). She had a high forehead, hypertelorism, downslanted palpebral fissures, deep-set eyes, thick

Characterization by array-CGH of an interstitial de novo tandem 6p21.2p22.1 duplication in a boy with epilepsy and developmental delay

We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3 Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region ( GABBR1, BRD2 and GRM4).

Prader–Willi syndrome phenocopy due to duplication of Xq21.1–q21.31, with array CGH of the critical region

We report on a 4-year-old male with an interstitial tandem duplication of Xq21.1-q21.31 who presented with clinical features of Prader-Willi syndrome (PWS). The duplication was maternally inherited. Abnormalities of the X chromosome have previously been reported in association with a PWS phenotype, but to date, specific duplications of Xq21.1-q21.31 have not. We refined the chromosomal breakpoints seen on initial G-banded karyotyping in our case with comparative genomic hybridization by microarray (array CGH). The duplication was between 11.1 and 14.4 Mb in length and overlaps with three loci to which mental retardation with PWS-like features have been previously mapped, showing the utility of array CGH in helping to identify candidate genes. We conclude that duplication of chromosomal region Xq21.1-q21.31 potentially results in a PWS-like phenotype. Reviewing the literature on similar duplications, we further conclude that distal Xq duplications can result in features typically seen in infants with PWS, while proximal duplications can result in features typically seen in older children and adults with PWS. Duplications of chromosome Xq should be considered in the differential diagnosis of PWS, especially in males.

Pure partial trisomy of 6p12.1–p22.1 secondary to a familial 12/6 insertion in two malformed babies

We describe two malformed infants with trisomy 6p12.1–p22.1 due to 12/6 interchromosomal insertion. The phenotypic data observed in these patients are compared chiefly with a case cytogenetically similar described by Villa et al. [A. Villa, E.G. Gomez, L. Rodriguez, R.H. Rastrollo, M.E. Martinez Tallo, M.L. Martinez-Frias, Interstitial tandem duplication of 6p: a case with partial trisomy (6)(p12p21.3), Am. J. Med. Genet. 90 (2000) 369–375]. All three infants are trisomic for a genomic segment which largely overlaps that reported as duplicated in previous cases, but with the addition of a more proximal segment, extending from 6p12 to 6p21. We suggest that some of their phenotypic anomalies are due to the trisomy of this chromosomal region. We also speculate on the possible role played by the TFAP2B (Transcription Factor AP2-beta) gene, which is one of the genes mapped on the duplicated segment.

442 Depletion of DNA methyltransferase (DNMT)1, and/or DNMT3b mediates growth arrest and apoptosis in lung and esophageal cancer cells

15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1–BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism.Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region.Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader–Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1–BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.

Molecularly defined interstitial tandem duplication 6p case with mild manifestations

Molecularly defined interstitial tandem duplication 6p case with mild manifestations

Molecularly defined interstitial tandem duplication 6p case with mild manifestations

An interstitial tandem duplication of 6p21.1-p22.2 was found in a girl at 11 months of age when she was evaluated for developmental delay. Previous cases reported with partial 6p duplication usually have involved terminal duplications, with breakpoints ranging from 6p11 to 6p25. Our patient exhibits a milder phenotype compared to the previously reported cases in the literature. Features that she has in common with the other cases include craniofacial anomalies, such as broad nasal bridge and bulbous tip, thin lips, incomplete development of the scapha helix bilaterally, mild spastic paraparesis of the lower extremities, gross motor delay, and mild cognitive delays.