De novo direct duplication of 15q15-->q24 in a newborn boy with mild manifestations

Duplication of distal 15q results in a recognizable clinical phenotype. We report here on a 25-day-old boy with a de novo interstitial duplication of chromosome region 15q15-q24. The manifestations in this patient are milder than those of previously described patients and include minor facial anomalies, velopharyngeal insufficiency, branchial cleft cyst, and hydronephrosis. Fluorescence in situ hybridization (FISH) using a chromosome 15 painting probe confirmed that the extra material is of chromosome 15 origin. Further analysis with the SNRPN probe demonstrated that the duplication is telomeric to the Prader-Willi/Angelman syndrome critical region. This case delineates a broader spectrum for patients with duplication 15q syndrome.     

A de novo 6q11—q15 duplication investigated by chromosome painting

A de novo interstitial duplication of the 6q11—q15 chromosome region, confirmed by the application of a chromosome 6 painting probe, was observed in a patient with craniofacial dymorphism, psychomotor retardation, cryptorchidism and hypospadias. Despite the publication of several cases showing partial trisomy 6q, to our knowledge the duplication of the proximal region q11-q15 has not previously been reported.     

Partial duplication of 3q (q25.1→q26.1) without the Brachmann-de Lange phenotype

Partial duplications of chromosome 3 have previously been reported to have phenotypic characteristics similar to Brachmann-de Lange syndrome (BDLS). We present the case of a 13-Year-old girl with an apparent duplication in the 3q25.1→q26.1 region but none of the manifestations commonly seen in BDLS. The chromosome 3 duplication was confirmed with a FISH painting probe of the involved region. These results suggest that the region critical for Brachmann-de Lange syndrome is not within the duplicated region of 3q25.1→q26.1. © 1993 Wiley-Liss, Inc.     

Analysis of 10 patients with duplications of 15q11q13 region and autism featuresCSCD

Objective: To analyze the clinical and genetic features of 10 unrelated patients with duplications of 15q11q13 region and autism features. Methods: Karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridiztion (FISH) were carried out for the patients and their parents. Results: Eight patients presented with a supernumerary marker chromosome (SMC) of unknown origin by G-banding analysis and triplication of the 15q11q13 region by high-resolution CMA analysis. Two remaining patients had normal karyotypes but duplications of the 15q11q13 region. All duplications have encompassed the Prader Willi/Angelman syndrome critical region (PWACR). Similar gains in copy number were not detected among the parents of the patients, suggesting a de novo origin for them. Analysis of SNP-array data of the family trios using Chromosome Analysis Suite Software found that the copy number gains have originated from the mothers. The diagnosis of 15q11q13 duplication syndrome was ascertained. For patients with SMC detected by karyotyping analysis, a FISH assay using probes specific for the 15q11q13 region showed that such SMC also derived from chromosome 15q11q13 region and contained two copy numbers, which was consistent with the result of CMA. Conclusion: Ten patients with autism and 15q11q13 duplications were identified with combined karyotyping, CMA and FISH analysis. A phenotype-genotype correlation was established. © 2018 West China University of Medical Sciences. All rights reserved.     

Interstitial duplications of chromosome region 15q11q13: Clinical and molecular characterization

Duplications of chromosome region 15q11q13 often occur as a supernumerary chromosome 15. Less frequently they occur as interstitial duplications [dup(15)]. We describe the clinical and molecular characteristics of three patients with de novo dup(15). The patients, two males and one female (ages 3–21 years), had nonspecific findings that included autistic behavior, hypotonia, and variable degrees of mental retardation. The extent, orientation, and parental origin of the duplications were assessed by fluorescent in situ hybridization, microsatellite analyses, and methylation status at D15S63. Two patients had large direct duplications of 15q11q13 [dir dup(15)(q11q13)] that extended through the entire Angelman syndrome/Prader-Willi syndrome (AS/PWS) chromosomal region. Their proximal and distal breaks, at D15S541 or D15S9 and between D15S12 and D15S24, respectively, were comparable to those found in the common AS/PWS deletions. This suggests that duplications and deletions may be the reciprocal product of an unequal recombination event. These two duplications were maternally derived, but the origin of the chromatids involved in the unequal crossing over in meiosis differs. In one patient, the duplication originated from two different maternal chromosomes, while in the other patient it arose from the same maternal chromosome. The third patient had a much smaller duplication that involved only D15S11 and parental origin could not be determined. There was no obvious correlation between phenotype and extent of the duplication in these patients. Am. J. Med. Genet. 79:82–89, 1998. © 1998 Wiley-Liss, Inc.     

Duplication of proximal 15q as a cause of Prader-Willi syndrome

We describe an apparent duplication of proximal 15q, i.e., 15q11q12 or 15q12q13 in two patients. Prometaphase chromosome analysis, C-banding and distamycin A/DAPI staining were used to exclude a translocation between the abnormal 15 homolog and another chromosome. The 2 patients have many manifestations of the Prader-Willi syndrome (PWS) including at least 5 of the following: obesity, compulsive eating, mental retardation, short stature, central hypotonia, hypogonadism, small hands and feet, hypopigmentation, and feeding problems in infancy. Results of high resolution chromosome analysis of the parents of both patients were normal. A comparison between these patients and 2 subjects from previous reports demonstrates phenotypic heterogeneity among the duplication 15q PWS patients. Two patients have the hypopigmentation seen in chromosomally normal and deletion PWS patients. These cases add to the variety of chromosome 15 aberrations which are associated with PWS.     

Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay

Interstitial duplications of proximal 15q containing the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region have been found in patients with autism or atypical autism. In these cases with an abnormal phenotype, the duplications were maternally derived. Paternal origin of the duplication has been associated with a normal phenotype. We report on a patient who presented with nonspecific developmental delay and partial agenesis of the rostral corpus callosum. Fluorescence in situ hybridization (FISH) studies using probes specific for the PWS/AS region demonstrated a double signal on one chromosome 15, indicating the presence of an interstitial duplication of proximal 15q involving the PWS/ AS region in the patient. Parental chromosomes were normal with FISH studies. Methylation analysis at exon alpha of the SNRPN locus showed a maternal band at 4.2 kb and a paternal band of apparent double intensity at 0.9 kb, suggestive of one copy of the maternal allele and two copies of the paternal allele in the patient. Microsatellite analysis was informative at the GABRB3 locus in the family, which showed the inheritance of two different paternal alleles and a maternal allele in the patient consistent with the origin of this duplication from an unequal crossing over between the two chromosome 15 homologs in the father. This is the first report of an abnormal phenotype associated with a paternally derived duplication of proximal 15q shown to contain the PWS/AS region by molecular techniques.     

Rearrangement of chromosome 15 in the region q11.2----q12 in an individual with obesity syndrome and her normal mother

Rearrangement of the proximal long arm of chromosome 15 have been found in most patients with the Prader-Willi syndrome (PWS) and in some with Angelman syndrome. We present an individual with syndromic obesity and her normal mother, who both have an abnormal chromosome 15. The proposita is a 26-year-old women with marked obesity, acanthosis, nigricans, short fingers, and severe cone degeneration of the retina. She has high plasma insulin levels, hypothyroidism, and an empty sella on CT scan. High-resolution chromosome banding demonstrated an increase in band 15q12. Further analysis showed the same abnormal 15 in her normal mother but not in her normal sister. This case and recent reports in the literature indicate that duplication of chromosome 15q in the PWS region may be associated with a syndrome of obesity, acanthosis nigricans, empty sella, and rodcore dystrophy as well as with a normal phenotype. Whether normal individuals with such a duplication carry increased risk of having offspring with an obesity syndrome is yet to be determined.     

15q24.1 BP4-BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24.2q24.3 duplication in a patient with epilepsy,psychomotor delay,overweight, ventricular arrhythmia

15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3–75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations.     

A 15q24 microduplication, reciprocal to the recently described 15q24 microdeletion, in a boy sharing clinical features with 15q24 microdeletion syndrome patients

A 15q24 microduplication, reciprocal to the minimal critical region for the recently described 15q24 microdeletion syndrome, was found in a 2-year-old boy by 244k Agilent oligoarray CGH analysis. The boy had global developmental delay and dysmorphic facial features, digital and genital abnormalities. The duplication was inherited from a healthy father, but was considered clinically significant, as the patient shared clinical features with 15q24 microdeletion syndrome patients. To our knowledge this is the first report of a patient with a 15q24 microduplication.     

Rearrangement of chromosome 15 in the region q11.2→q12 in an individual with obesity syndrome and her normal mother

Rearrangements of the proximal long arm of chromosome 15 have been found in most patients with the Prader-Willi syndrome (PWS) and in some with Angelman syndrome. We present an individual with syndromic obesity and her normal mother, who both have an abnormal chromosome 15. The proposita is a 26-year-old woman with marked obesity, acanthosis nigricans, short fingers, and severe cone degeneration of the retina. She has high plasma insulin levels, hypothyroidism, and an empty sella on CT scan. High-resolution chromosome banding demonstrated an increase in band 15q12. Further analysis showed the same abnormal 15 in her normal mother but not in her normal sister. This case and recent reports in the literature indicate that duplications of chromosome 15q in the PWS region may be associated with a syndrome of obesity, acanthosis nigricans, empty sella, and rodcore dystrophy as well as with a normal phenotype. Whether normal individuals with such a duplication carry increased risk of having offspring with an obesity syndrome is yet to be determined.     

The evaluation of 15q proximal duplications by FISH

Six patients from the clinical cytogenetics laboratory identified as having the normal variant dup(15)(q12) were further evaluated using fluorescence in situ hybridization (FISH). The purpose of this study was to ascertain whether any of the Prader–Willi/Angelman Chromosome Region ( PWCR and ANCR , respectively) loci were duplicated in these patients. The results indicated that the patients could be categorized into two groups. The first group showed no duplication of the PWCR/ANCR loci and appeared to belong to the dup(15)(q12) class which is phenotypically silent and is therefore called the normal variant. The second group also showed no duplication of the PWCR/ANCR loci, but had a large alpha satellite variant with D15Z. It is hypothesized that these patients do not have a duplication of 15q12 but rather a centromeric variant which mimics the dup(15)(q12). This study confirms the importance of evaluating apparent variations in the proximal region of chromosome 15 with FISH.     

15q duplication associated with autism in a multiplex family with a familial cryptic translocation t(14;15)(q11.2;q13.3) detected using array-CGH

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic aetiology. In approximately 1% of cases, duplication of the 15q11-13 region has been reported. We report the clinical, array-comparative genomic hybridization (CGH) and cytogenetic evaluation of two individuals from a multiplex family demonstrating autism due to a maternally inherited gain of 15q11-13. Our findings indicate that unlike most 15q11-13 gains, which are caused by interstitial duplication of this region or supernumerary marker chromosomes deriving from proximal 15q, the 15q gain in this family is the result of abnormal segregation of a cryptic familial translocation with breakpoints at 14q11.2 and 15q13.3. The affected members of this family were found to have a normal karyotype at >550 band resolution. This translocation was identified using the 1-Mb resolution whole genome array (Spectral Genomics). The affected individuals have a gain of seven clones from proximal 15q, a loss of two clones from proximal 14q and a gain of two clones from 6q. Fluorescent in situ hybridization (FISH) analysis with clones from chromosomes 14 and 15, combined with DAPI reverse banding, showed an abnormal karyotype with one normal chromosome 15 and the der(15) t(14;15)(q11.2.;q13.3), resulting in the gain of proximal 15q and the loss of proximal 14q in affected individuals. The duplication of two clones from 6q in the affected subjects was also found in unaffected members of the family. Our findings suggest that the gain of 15q in autism may in some cases be due to cryptic translocations with breakpoints in the pericentromic regions of chromosome 15 and a different acrocentric chromosome. Variation in the size of pericentromic regions of any acrocentric chromosome may justify karyotype and FISH studies of autistic probands and their parents using probes from the 15q proximal region to determine recurrence risk for autism in some families.     

Patient with terminal duplication 3q and terminal deletion 5q: comparison with the 3q duplication syndrome and distal 5q deletion syndrome

Partial duplication of chromosome 3q is a well-described condition of multiple congenital anomalies and developmental delay that resembles the Brachmann-de Lange syndrome. Similarly, an emerging phenotype of a distal 5q deletion syndrome has recently been described. The combination of both chromosome abnormalities has not been previously described. We report on a child with both a de novo duplication of distal 3q (q27 --> qter) and terminal deletion of 5q (q35.2 --> qter). The patient had facial anomalies, hypoplastic toenails, lymphedema of the dorsum of the feet, type I Chiari malformation, a seizure disorder, and moderate developmental delays. The phenotype is compared and contrasted to the few reports of patients with similar terminal 3q duplications and 5q deletions. Our patient did not have the characteristic phenotype of the 3q duplication syndrome, suggesting that the chromosome region responsible for this phenotype is more proximal than the terminal 3q27 region. In addition, comparison with three other reported cases of terminal 5q35 deletions suggests a possible association of terminal 5q deletions with central nervous system (CNS) structural abnormalities.     

Mosaicism del(22)(q11.2q11.2)/dup(22)(q11.2q11.2) in a patient with features of 22q11.2 deletion syndrome

The chromosome 22q11 region is prone to rearrangements, including deletions and duplications, due to the presence of multiple low copy repeats (LCRs). DiGeorge/velo-cardio-facial syndrome is the most common microdeletion syndrome with more than 90% of patients having a common 3-Mb deletion of 22q11.2 secondary to non-homologous recombination of flanking LCRs. Meiotic reciprocal events caused by LCR-mediated rearrangement should theoretically lead to an equal number of deletions and duplications. Duplications of this region, however, have been infrequently reported and vary in size from 3 to 6 Mb. This discrepancy may be explained by the difficulty in detecting the duplication and the variable, sometimes quite mild phenotype. This newly described 22q duplication syndrome is characterized by palatal defects, cognitive deficits, minor ear anomalies, and characteristic facial features. We report on a male with truncus arteriosus and an interrupted aortic arch, immunodeficiency, and hypocalcemia. The patient is mosaic for two abnormal cell lines: a deletion [del(22)(q11.2q11.2)] found in 11 cells and a duplication [dup(22)(q11.2q11.2)] found in 9 cells. Molecular cytogenetic analysis in our patient revealed a 1.5 Mb deletion/duplication, the first duplication reported of this size. Deletion/duplication mosaicism, which is rare, has been reported in a number of cases involving many different chromosome segments. We present the clinical phenotype of our patient in comparison to the phenotypes seen in patients with the 22q11.2 deletion or duplication alone. We propose that this rearrangement arose by a mitotic event involving unequal crossover in an early mitotic division facilitated by LCRs.     

Unusual clinical features in an Angelman syndrome patient with uniparental disomy due to a translocation 15q15q

We had previously described a patient with an overgrowth syndrome and the chromosome constitution 45,XY,t(15q15q) (Wajntal et al., DNA Cell Biol 1993: 12: 227–231). Clinical reassessment and the use of molecular studies, including methylation analysis with an SNRPN probe, microsatellite analyses of D15S11 , GABRB3 and D15S113 loci, and fluorescence in situ hybridization (FISH) using the SNRPN and GABRB3 probes, are consistent with a diagnosis of Angelman syndrome (AS) due to paternal isodisomy. This is the fourth report case of a translocation 15q15q with paternal uniparental disomy (UPD). Our findings suggest that some patients with clinical features of AS have hyperphagia and obesity with overgrowth, and that these features should not rule out a diagnosis of AS.     

Syndromal obesity due to paternal duplication 6(q24.3-q27)

The likelihood of a paternally expressing imprinted gene in chromosome region 6(q23-24) has been highlighted by cases of transient neonatal diabetes mellitus (TNDM) in which paternal uniparental disomy (UPD) for chromosome 6 or paternal duplication 6(q23-qter) was detected. We present the case of a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, eye abnormality, small mouth, and obesity (without hyperphagia) beginning in mid-childhood. The perinatal and neonatal histories were normal. The patient had a duplication within 6q. Fluorescence in situ hybrisation studies were performed with single and dual hybridisations using a chromosome 6 library probe, short and long arm subregional probes, 6q23-24, 6q25.3-6qter locus-specific probes, and a 6q telomere probe. The hybridisation results defined an inverted duplication of 6q24.3 to 6q27. DNA studies with microsatellite markers from 6p and 6q showed regular biparental inheritance of chromosome 6 and confirmed that the duplication was paternal in origin. Our patient appears to be the first one known to have paternal duplication of chromosome area 6(q24-q27) who did not have TNDM as an infant. He has remained nondiabetic, although obesity, without hyperphagia, has been a constant problem since its onset in mid-childhood. Am. J. Med. Genet. 84:125–131, 1999. © 1999 Wiley-Liss, Inc.     

Duplication 15q as the sole anomaly in an acute promyelocytic leukemia patient without t(15;17)

We present a unique chromosomal abnormality found in a patient with acute myeloblastic leukemia of French-American-British subtype M3. The patient was referred for an evaluation of a chromosomal anomaly exclusively associated with FAB M3 or acute promyelocytic leukemia: a translocation between chromosomes 15 and 17, t(15;17)(q22;q21.1). Neither t(15;17) nor rearrangement of RARalpha was detected by routine G-banded chromosome as well as fluorescence in situ hybridization analysis using the commercial dual-color PML/RARalpha translocation probe and the RARalpha probe, a break apart rearrangement dual-color probe. Instead of the typical rearrangement between chromosomes 15 and 17, all cells analyzed had a duplication of the segment of chromosome 15 between bands 15q15 and 15q26.     

Additional complexity on human chromosome 15q: identification of a set of newly recognized duplicons (LCR15) on 15q11-q13, 15q24, and 15q26

Several cytogenetic alterations affect the distal part of the long arm of human chromosome 15, including recurrent rearrangements between 12p13 and 15q25, which cause congenital fibrosarcoma (CFS). We present here the construction of a BAC/PAC contig map that spans 2 Mb from the neurotrophin-3 receptor (NTRK3) gene region on 15q25.3 to the proximal end of the Bloom's syndrome region on 15q26.1, and the identification of a set of new chromosome 15 duplicons. The contig reveals the existence of several regions of sequence similarity with other chromosomes (6q, 7p, and 12p) and with other 15q cytogenetic bands (15q11-q13 and 15q24). One region of similarity maps on 15q11-q13, close to the Prader-Willi/Angelman syndromes (PWS/AS) imprinting center. The 12p similar sequence maps on 12p13, at a distance to the ets variant 6 (ETV6) gene that is equivalent on 15q26.1 to the distance to the NTRK3 gene. These two genes are the targets of the CFS recurrent translocations, suggesting that misalignments between these two chromosomes regions could facilitate recombination. The most striking similarity identified is based on a low copy repeat sequence, mainly present on human chromosome 15 (LCR15), which could be considered a newly recognized duplicon. At least 10 copies of this duplicon are present on chromosome 15, mainly on 15q24 and 15q26. One copy is located close to a HERC2 sequence on the distal end of the PWS/AS region, three around the lysyl oxidase-like (LOXL1) gene on 15q24, and three on 15q26, one of which close to the IQ motif containing GTPase-activating protein 1 (IQGAP1) gene on 15q26.1. These LCR15 span between 13 and 22 kb and contain high identities with the golgin-like protein (GLP) and the SH3 domain-containing protein (SH3P18) gene sequences and have the characteristics of duplicons. Because duplicons flank chromosome regions that are rearranged in human genomic disorders, the LCR15 described here could represent new elements of rearrangements affecting different regions of human chromosome 15q.     

A family with a grand-maternally derived interstitial duplication of proximal 15q

About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11-q13 region. These abnormalities can be detected by routine G-banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11-q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language-based learning disabilities.