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Partial karyotype and FISH analysis. Patient 1: (a) partial karyotype of derivative chromosome 15. FISH study using probes for SNRPN locus (orange, short arrows) at 15q11q13 and PML locus (green, long arrows) at 15q22: (b) interphase cells and (c) SMC15. Patient 2: (d) partial karyotype of inv dup(15), FISH using SNRPN and PML probes: (e) interphase cells and (f) inv dup(15q).
Source publication
Background
The proximal chromosome 15q is prone to unequal crossover, leading to rearrangements. Although 15q11q13 duplications are common in patients with developmental delays and mental impairment, 15q aneusomies resulting in greater or equal to 4 copies of 15q11q13 are rare and no pentasomy 15q11q13 has been reported in the literature. Thus far,...
Contexts in source publication
Context 1
... chromosome analysis of peripheral blood revealed each patient had a SMC15: a rea(15)(q11) or 47,XY,+rea (15)(q11) in patient 1 and an inv dup(15)(q11q13) or 47,XY, +inv dup(15)(q11q13) in patient 2 (Figure 2). Parental cyto- genetic studies were normal. ...Context 2
... annotations were determined using build GRCh37 (Figure 4). FISH using the SNRPN probe (Abbott Mo- lecular, USA) showed that in addition to 2 signals on normal chromosome 15 homologues, the SMC15 from patient 1 had 3 signals (Figures 2b and 2c), and the inv dup(15q) from patient 2 had 2 signals (Figures 2e and 2f ), confirming the array findings of pentasomy and tet- rasomy 15q11q13 in patients 1 and 2, respectively. ...Context 3
... annotations were determined using build GRCh37 (Figure 4). FISH using the SNRPN probe (Abbott Mo- lecular, USA) showed that in addition to 2 signals on normal chromosome 15 homologues, the SMC15 from patient 1 had 3 signals (Figures 2b and 2c), and the inv dup(15q) from patient 2 had 2 signals (Figures 2e and 2f ), confirming the array findings of pentasomy and tet- rasomy 15q11q13 in patients 1 and 2, respectively. ...Similar publications
Large amounts of low copy number repeats in the 15q11.2q13.3 chromosomal region increase the possibility of misalignments and unequal crossover during meiosis in this region, leading to deletions, duplications, triplications and supernumerary chromosomes. Most of the reported cases with epilepsy, autism and Prader-Willi/Angelman syndrome are in ass...
Citations
... The most common aneuploidies are trisomies (Tr; presence of one extra copy of a certain chromosome) and monosomies (loss of one copy in a pair of homologous chromosomes). However, double trisomies, tetrasomy, pentasomy and even hexasomy of autosomes are also present in some types of cancers [1], multiple copies of large chromosome fragments are found in patients with mental disorders [2] and multiple copies of Y and X chromosome are associated with severe development defects [3]. Autosomal trisomy is the most widespread type of aneuploidy (about 60% of clinical cases) associated with miscarriage [4,5] and abnormalities of embryonic development [6]. ...
Trisomy is the presence of one extra copy of an entire chromosome or its part in a cell nucleus. In humans, autosomal trisomies are associated with severe developmental abnormalities leading to embryonic lethality, miscarriage or pronounced deviations of various organs and systems at birth. Trisomies are characterized by alterations in gene expression level, not exclusively on the trisomic chromosome, but throughout the genome. Here, we applied the high-throughput chromosome conformation capture technique (Hi-C) to study chromatin 3D structure in human chorion cells carrying either additional chromosome 13 (Patau syndrome) or chromosome 16 and in cultured fibroblasts with extra chromosome 18 (Edwards syndrome). The presence of extra chromosomes results in systematic changes of contact frequencies between small and large chromosomes. Analyzing the behavior of individual chromosomes, we found that a limited number of chromosomes change their contact patterns stochastically in trisomic cells and that it could be associated with lamina-associated domains (LAD) and gene content. For trisomy 13 and 18, but not for trisomy 16, the proportion of compacted loci on a chromosome is correlated with LAD content. We also found that regions of the genome that become more compact in trisomic cells are enriched in housekeeping genes, indicating a possible decrease in chromatin accessibility and transcription level of these genes. These results provide a framework for understanding the mechanisms of pan-genome transcription dysregulation in trisomies in the context of chromatin spatial organization.
... In another report, both patients had a moderate intellectual disability, behavioral disorder with aggressive and autistic features, epilepsy, scoliosis, and truncal obesity (52). 15q Duplication A total of 12 papers found in our search, report on 86 patients with a 15q duplication (13,(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). Thirty patients were described in a single paper (13). ...
Prader-Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader-Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf-Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion,15q duplication, 19p deletion, fragile X syndrome and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%) and psycho-behavioral problems (53%).In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.
... The number of idic (15) reported across different cases has varied. Partial tetrasomy 15q, which is caused by one idic (15), is relatively common (approximately 80% of cases) [7,8,[11][12][13][14][15][16][17][18][19], and partial hexasomy 15q, which is caused by one or two idic (15) or tricentric der (15), has also been occasionally described [9,[20][21][22][23]. However, individuals who carry more than two idic(15) have rarely been reported. ...
... Nevertheless, a single idic(15) that included four extra copies of 15q11-q13 resulting in hexasomy of 15q, has also been reported [22]. To date, different copy number variations (CNVs) of the 15q11-q13 fragment have been observed to range from 3 to 6 copies, resulting in triplication [15,30], tetrasomy [11,12,[16][17][18], pentasomy [14] and hexasomy [9,[21][22][23]. Tetrasomy 15q, containing one extra idic (15), is relatively common. ...
Background
Small supernumerary marker chromosomes (sSMCs) are common structurally abnormal chromosomes that occur in 0.288% of cases of mental retardation. Isodicentric 15 (idic(15)) is common in sSMCs and usually leads to a rare chromosome disorder with distinctive clinical phenotypes, including early central hypotonia, developmental delay, epilepsy, and autistic behavior. It was previously shown that the partial tetrasomy 15q and partial hexasomy 15q syndromes are usually caused by one and two extra idic(15), respectively. Karyotypes containing a mosaic partial octosomy 15q resulting from three extra idic(15) have rarely been reported. Case presentationTwo patients with profound intellectual impairment, development delay and hyperpigmentation were recruited for this study. The phenotype was relatively more severe in patient 1 than in patient 2. Conventional cytogenetic analysis of peripheral blood obtained from patients 1 and 2 revealed rare mosaic karyotypes containing sSMCs, i.e., mos 49,XX,+mar × 3[83]/48,XX,+mar × 2[7]/46,XX[10] and mos 48,XX,+mar × 2[72]/47,XX,+mar[28], respectively. The results of analyses of copy number variation (CNV) and fluorescence in situ hybridization (FISH) analyses, showed that the sSMCs were found to be idic(15) involving the Prader-Willi/Angelman Syndrome Critical Region (PWACR) genes and the P gene, with duplication sizes of 6.3 Mb and 9.7 Mb, respectively. DNA fingerprinting analysis of patient 1 showed a maternal origin for the idic(15). Both patients had mosaic idic(15) karyotypes: patient 1 had cells with a 15q partial octosomy (83%), and patient 2 had cells with a 15q partial hexasomy (72%). Conclusions
We detected two rare mosaic idic(15) karyotypes that were associated with congenital abnormalities, including a rare mosaic octosomy of 15q11-q13. Our cases further validate the notion that the phenotypic severity is correlated with the level of mosaicism and the dosage effect of related genes in the proximal 15q.
... В нем часто формируются точки разрыва с последующим формированием маркерных хромосом, что приводит к тетрасомии 15p и частично 15q. Клиническая и цитогенетическая картина, характерная для этого пациента, соответствует синдрому дупликации 15q11-q13, который зачастую сопровождается синдромами Прадера-Вилли или Ангельмана, так как затронут критический район для этих синдромов [6][7][8][9]. Особо следует отметить увеличение копийности генов рРНК, при котором на маркерной хромосоме экспрессируются дополнительные копии, что также может вносить вклад в развитие клинической картины. Ранее показано, что правильная сборка рибосом очень важна для дифференцировки нервных клеток, в частности для формирования дендритов [10], при этом нарушения синтеза рРНК приводили к развитию нейродегенерации у мышей [11]. ...
... In this study, we present copy number changes and methylation pattern from an isodicentric chromosome 15 and a small ring chromosome 15. Review of literature found five reports with combined copy number and methylation analyses on 34 cases of sSMC(15)s and two cases of small ring chromosome 15 [17,[22][23][24][25]. These results demonstrate that combined karyotype, FISH, aCGH and MS-MPLA analyses could be used in a clinical setting effectively to define genomic structure, parental origin and level of mosaicism for sSMC (15)s. ...
... Currently, more than 1300 similar sSMC(15) cases (published or not) are collected in the online sSMC database (http://ssmc-tl.com/sSMC.html). Carefully checking the website and review of literatures found five reports with combined karyotype, aCGH/SNP and methylation analyses on 34 cases of idic (15) and two cases of small r(15) [17,[22][23][24][25]. The genomic structures and methylation patterns from these cases and our two cases are summarized in Table 1. ...
... Therefore, for small supernumerary r(15), ring structure instability and secondary rearrangements should be considered. Our two cases and almost all reported de novo cases of idic(15)s showed a genomic structure including PWACR and a methylation pattern of maternal origin [5][6][7][8][9][10][11][12][13][14][15][16][17][22][23][24][25]. As reported from previous analyses, clinical phenotypes for sSMC (15)s are related with the duplication region containing the PWACR and the maternally derived homologue of chromosome 15q [13,17]. ...
Background:
The low copy repeats (LCRs) in chromosome 15q11-q13 have been recognized as breakpoints (BP) for not only intrachromosomal deletions and duplications but also small supernumerary marker chromosomes 15, sSMC(15)s, in the forms of isodicentric chromosome or small ring chromosome. Further characterization of copy number changes and methylation patterns in these sSMC(15)s could lead to better understanding of their phenotypic consequences.
Methods:
Routine G-band karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) analysis and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay were performed on two Chinese patients with a sSMC(15).
Results:
Patient 1 showed an isodicentric 15, idic(15)(q13), containing symmetrically two copies of a 7.7 Mb segment of the 15q11-q13 region by a BP3::BP3 fusion. Patient 2 showed a ring chromosome 15, r(15)(q13), with alternative one-copy and two-copy segments spanning a 12.3 Mb region. The defined methylation pattern indicated that the idic(15)(q13) and the r(15)(q13) were maternally derived.
Conclusions:
Results from these two cases and other reported cases from literature indicated that combined karyotyping, aCGH and MS-MLPA analyses are effective to define the copy number changes and methylation patterns for sSMC(15)s in a clinical setting. The characterized genomic structure and epigenetic pattern of sSMC(15)s could lead to further gene expression profiling for better phenotype correlation.
... These duplications occur mostly in two forms, including an extra isodicentric 15 (idic (15)) chromosome or an interstitial duplication 15. Based on previous literature data we can assume that patients with idic (15) of paternal origin seem to have normal development however, maternal aberrations can lead to developmental problems [4,20,21]. In most of the cases the 15q duplication syndrome is not inherited, but occurs randomly during the formation of reproductive cells. ...
... Examinations of the syndrome could not show an obvious correlation between the severity of the symptoms and the size of the duplicated region. Copy number changes of this chromosomal region from three to six have been reported in the literature [4,22,21]. ...
... Hypotonia, delayed motor milestones (sitting up, walking), delayed language development, progressed hypertonia, and similar facial characteristics, including flat nasal bridge, epicanthic and hyperteloristic eyes in Patient 1. can assume a 15q duplication syndrome that affected the 15q11.2q13.3 (22,765,445,252) chromosomal region [21]. In addition to the symptoms were seen in Patient 1., Patient 2. represented typical Angelman like features including After uneventful prenatal period, both of our patients had normal birth weight. ...
Large amounts of low copy number repeats in the 15q11.2q13.3 chromosomal region increase the possibility of misalignments and unequal crossover during meiosis in this region, leading to deletions, duplications, triplications and supernumerary chromosomes. Most of the reported cases with epilepsy, autism and Prader-Willi/Angelman syndrome are in association with rearrangements of the proximal long arm of chromosome 15.
Here we report the first two unrelated Hungarian patients with the same epileptic and dysmorphic features, who were investigated by array comparative genomic hybridization (array CGH). By G-banded karyotype followed by FISH and array CGH we could detect partial tetrasomy of the 15q11.2q13.3 chromosomal region, supporting proximal 15q duplication syndrome. Findings of the array CGH gave fully explanation of the phenotypic features of these patients, including epileptic seizures, delayed development, hyperactivity and craniofacial dysmorphic signs. Besides the described features of isodicentric (15) (idic(15)) syndrome Patient 1. suffered from bigeminic extrasystoles and had postnatal growth retardation, which had been published only in a few articles.
Dosage effect of some genes in the concerned genomic region is known, but several genes have no evidence to have dosage dependence. Our results expanded the previous literature data. We assume dosage dependence in the case of CHRNA7 and OTUD7A, which might be involved in growth regulation. On the other hand increased dosage of the KLF13 gene seems to have no direct causal relationship with heart morphology. The genomic environment of the affected genes may be responsible for the observed phenotype.
... The analysis is based on 33 patients investigated in Peking Union Medical College Hospital from 1994 to 2014 (male 18, female 15, aged 5 months to 18 years) and 87 cases with reported PWS from other tertiary hospitals in Mainland China (male 55, female 32, aged 8 days to 18 years). We retrospectively obtained the recorded growth parameters (length/height and weight) from charts of our patients or retrieved from Pubmed Fong et al. 2012;Ma et al. 2012;Yang et al. 2013;Yu et al. 2013;Zhu et al. 2013;Lu et al. 2014a) (http://www.ncbi.nlm.nih.gov/pubmed) and China National Knowledge Infrastructure (http://www.cnki.net). In all patients considered for this study, the diagnosis was either confirmed by stringent clinical diagnostic criteria (Holm et al. 1993) or by genetic investigation (n = 39; 32.5%). ...
To investigate the spontaneous development of growth and weight gain of patients with Prader-Willi syndrome (PWS) in Mainland China.
We retrospectively analyzed120 cases of PWS diagnosed from 1994 to 2014 in Mainland China. Scatter diagram of the growth data was compared to standardized growth curve.
The length at birth is similar to normal population and the mean birth weight is under the50th centile of normal population. Heights in 43% (27/62) of patients had dropped off below the 3(rd) centile of their peers after 5 years of age. Weights in 65.9% (58/88) of patients had exceeded the 97(th) centile of their peers after 3 years of age. Early obesity is obvious in 92.9% (66/71) of patients with BMI up the 97(th) centile of their peers from 2-3 years of age. Final mean height is 149.3±11.2cmfor females(n=7) and 146.2±9.8cm for males(n=6), showing 11.3cm and 26.6cm below the average height for normal Chinese girls and boys.
The growth pattern of PWS in Mainland China is comparable to those in Caucasians. Early intervention with recombinant human growth hormone is warranted considering the early onset of growth retardation and obesity.
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... The high frequency of such cases gave rise to a clinically recognizable disorder called 15q duplication syndrome, with some common neurobehavioural phenotypes [4]. Copy numbers of three, four, five and six have all been reported for this region [5][6][7]. ...
Background
The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism. We performed analyses to delineate their dosage in the 15q region, determine whether the patients’ dosage correlates with phenotypic severity, and whether genes in the amplified regions are significantly associated with identified functional networks.
Results
For the proximal region of 15q, molecular cytogenetic analysis with Agilent oligonucleotide array showed a copy number of 3 for Patient 1 and a copy number of 4 for Patient 2. Fluorescent in situ hybridization analysis of Patient 2 showed two different populations of cells with different marker chromosomes. Methylation analysis of the amplified region showed that the extra copies of small nuclear ribonucleoprotein polypeptide N gene were of maternal origin. Phenotypic severity did not correlate with the size and dosage of 15q, or whether the amplification is interstitial or in the form of a supernumerary marker. Pathway analysis showed that in Patient 2, the main functional networks that are affected by the genes from the duplicated/triplicated regions are developmental disorder, neurological disease and hereditary disease.
Conclusions
The 15q11-q13 gains that were found in both patients could explain their phenotypic presentations. This report expands the cohort of patients for which 15q11-q13 duplications are molecularly characterized.
Marker chromosomes are structurally abnormal chromosomes that may be supernumerary in karyotype or replace one of the chromosomes. Marker chromosomes very frequently can be a cause of different pathologies, including a intellectual disability. This study considers the molecular cytogenetic analysis of an acrocentric marker chromosome in a patient with autism and a intellectual disability. With the help of the painting probe localization of human chromosomes, its origin from the pericentromeric regions of the p and q arms of chromosome 15 is shown. For more detailed detection of the region of origin of this chromosome, its microdissection following localization on both healthy control and patient metaphase plates was carried out. Its origin from the nucleolus-containing chromosome 15 is confirmed. Because of the rDNA-containing plasmid localization, two of the ribosome RNA gene clusters were detected on the patient’s chromosomes. Ag-NOR staining showed that both clusters are active. A possible contribution of the revealed chromosome pathology in clinical picture formation is discussed.
Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.
