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A Nine-Month-Old Boy With Isodicentric Chromosome 15: A Case Report

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Doug Ho Park
Doug Ho Park
Doug Ho Park
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Seonggyu Lim
Seonggyu Lim
Seonggyu Lim
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Eun Sook Park at Yonsei University
Eun Sook Park
Eun Geol Sim at Yonsei University Hospital
Eun Geol Sim
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Abstract and Figures

Isodicentric chromosome 15 [idic(15)] is a rare chromosomal abnormality that occurs due to inverted duplication of chromosome 15q. It is associated with many clinical findings such as early central hypotonia, developmental delay, cognitive dysfunction, autism spectrum disorders, and seizure. Delayed development is a common problem referred to pediatric rehabilitation clinics. A 9-month-old boy with delayed development was referred to our clinic for assessment and treatment. On chromosomal analysis, he was diagnosed as idic(15) syndrome with 47,XY,+idic(15)(q12) on karyotyping. Herein we describe his clinical manifestations and provide a brief review of the related literature.
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A Nine-Month-Old Boy With Isodicentric
Chromosome 15: A Case Report
Doug Ho Park, MD, Seonggyu Lim, MD, Eun Sook Park, MD, Eun Geol Sim, MD
Department of Rehabilitation Medicine and Research Institute of Rehabilitation Medicine,
Yonsei University College of Medicine, Seoul, Korea
Isodicentric chromosome 15 [idic(15)] is a rare chromosomal abnormality that occurs due to inverted duplication
of chromosome 15q. It is associated with many clinical findings such as early central hypotonia, developmental
delay, cognitive dysfunction, autism spectrum disorders, and seizure. Delayed development is a common
problem referred to pediatric rehabilitation clinics. A 9-month-old boy with delayed development was referred to
our clinic for assessment and treatment. On chromosomal analysis, he was diagnosed as idic(15) syndrome with
47,XY,+idic(15)(q12) on karyotyping. Herein we describe his clinical manifestations and provide a brief review of
the related literature.
Keywords
Chromosomal abnormality, Developmental delay disorders, Tetrasomy 15q
Annals of Rehabilitation Medicine
Case Report
Ann Rehabil Med 2013;37(2):291-294
pISSN: 2234-0645 • eISSN: 2234-0653
http://dx.doi.org/10.5535/arm.2013.37.2.291
INTRODUCTION
The chromosome region 15q11
—
q13 is known for its
instability and is highly susceptible to genomic rear-
rangements [1]. Many rearrangements may occur in this
imprinted segment such as deletions associated either
with Angelman syndrome (AS) or Prader-Willi syn-
drome (PWS) according to parental origin; these involve
translocations, inversions, and supernumerary marker
chromosomes formed by the inverted duplication of
chromosome 15 [Inv dup(15)] [2]. Inv dup(15) syndrome
is the most common of the heterogeneous group of extra-
structurally abnormal chromosomes [3].
Inv dup(15) or isodicentric chromosome 15 [idic(15)]
displays distinctive clinical findings represented by hy-
potonia, developmental delay, mental retardations, dif-
ficulty with controlling epilepsy, autism, and autistic like
behavior. It can thus be clinically suspected prior to cyto-
genetic confirmation [4].
We present a case of idic(15) syndrome in a 9-month-
old boy who was referred to our clinic for delayed devel-
opment. The clinical features of this syndrome in this
early period have been rarely reported. In addition, the
youngest reported case of idic(15) syndrome was in an
11 months old [5] and no cases of this syndrome have
been reported in Korea, to the best of our knowledge. We
therefore report a case of idic(15) syndrome and provide
a brief literature review.
CASE REPORT
A 9-month-old boy visited our clinic with delayed de-
Received March 16, 2012; Accepted June 13, 2012
Corresponding author: Seonggyu Lim
Department and Research Institute of Rehabilitation Medicine, Yonsei
University College of Medicine, 50 Younsei-ro, Seodaemun-gu, Seoul
120-749, Korea
Tel: +82-2-2227-2396, Fax: +82-2-363-2795, E-mail: NYMPH-SG@yuhs.ac
This is an open-access article distributed under the terms of the Creative
Commons Attribution Non-Commercial License (http://creativecommons.
org/licenses/by-nc/3.0) which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original work is
properly cited.
Copyright © 2013 by Korean Academy of Rehabilitation Medicine
Doug Ho Park, et al.
292
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velopment. He was born at term by normal delivery with
birth weight of 3.7 kg after an uneventful pregnancy. The
family history was non-contributory. There were no no-
table prenatal and immediately postnatal problems. He
had been taken to another clinic at four months because
he could not hold his head. Brain magnetic resonance
image scan, thyroid function test, and metabolic work
ups were done at that time with normal results. At nine
months old, he visited our clinic due to his persistent de-
velopmental problems. Minor craniofacial dysmorphism
involving mildly deep-set eyes, downslanting palpebrae,
microcephaly, and hypotonic face were observed (Fig.
1). On physical examination, there were no abnormal
neurological signs such as persistent primitive reflex,
ankle clonus, Babinski’s sign or hyperactive deep tendon
reflexes. Diffuse hypotonia was noted. He could hold his
head at six months and sat with support at nine months,
but he could not sit without support nor crawl recipro-
cally at that time. He could reach with his arm to get a toy
with palmar grasp. He was babbling and attentive during
play, also was able to share enjoyment, to pleasure with
other people, and to make eye to eye contact. Stereotyped
movements such as repetitive hand twisting or head
turning and hand wringing were not observed. He had
a Mental Developmental Index (MDI) score of 74 and a
Psychomotor Developmental Index (PDI) score of 51 on
Bayley Scales of Infant Development II tests and a social
intelligence quotient (SQ) of 79.3 on the social maturity
scale. His subcategorical development was estimated at
four to five months in the cognitive area, four months
in the language and motor areas, and six months in the
social areas. On chromosomal study, chromosomal ab-
normality of 47,XY,+idic(15)(q12) was identified (Fig. 2).
Chromosomal analysis for his parents was strongly rec-
ommended but this was refused. He had physical and oc-
cupational therapy in order to reduce his developmental
delay. He sat without support at 11 months, could crawl
at 13 months, came to walk along the furniture at 17
months, and stood alone for a few seconds at 19 months.
Psychological evaluation at this point showed scores
below 50 on both the MDI and PDI of the Bayley scale
and the SQ of 68.3 for social maturity. His overall devel-
opmental lags were seven months in the social and lan-
guage areas, and eight to nine months in other areas. On
the Childhood Autism Rating Scale (CARS), his score was
15 and he did not show any distinctive autism or autistic
like behavior. At 19 months he had no history of clinically
notable seizure and his electroencephalography (EEG)
findings were normal.
Fig. 1. The boy shows some facial dysmorphism includ-
ing downslanting palpebral fissures, deep-set eyes and
microcephaly.
Fig. 2. Karyotyping of subject shows isodicentric chromo-
some 15 [idic(15)]. (A) Idic(15) is indicated by an arrow.
(B) Comparison of iIdic(15) with normal chromosome 15.
Two centromeres and q12 bands can be seen in Idic(15).
A Nine-Month-Old Boy With Isodicentric Chromosome 15
293
www.e-arm.org
DISCUSSION
Isodicentric 15 syndrome, also called idic(15) or inv
dup(15), is a chromosome abnormality that results from
duplications of chromosome 15q11
—
q13. Individuals with
idic(15) are typically born with 47 chromosomes, with
the extra chromosome being made up of a piece of chro-
mosome number 15 that has been duplicated end to end
like a mirror image [3]. The incidence of this syndrome
is not fully known but is estimated to be 1 in 30,000 with
a sex ratio of almost 1 [4]. Generally this syndrome is not
inherited and occurs de novo [4,6].
There is wide range of severity in the developmental
problems experienced by individuals with idic(15) syn-
drome. Various genetic mechanisms have been hypothe-
sized to explain this clinical heterogeneity, including the
size of chromosomal duplication, dosage effect of genes
in this region and the imprinting mechanism. In most
cases, the maternally inherited aberration of chromo-
some 15q11
—
q13 seems to be pathogenic [4].
The clinical features of idic(15) syndrome consist of
severe developmental delay and intellectual disorder
(ID), speech impairment, epilepsy, altered behavior, dif-
fuse hypotonia, and minor craniofacial dysmorphism.
Diffuse hypotonia, developmental delay, and intellec-
tual disorder affect all individuals with idic(15). ID has
been found to be severe to profound in 85% and mild to
moderate in 15% of cases [1,4]. The ages of acquisition
of motor milestones are rarely reported in the literature.
However it seems that sitting is generally achieved be-
tween 10 and 20 months of age and walking between two
and three years [4,7]. Many children with idic(15) share
similar facial characteristics including a flat nasal bridge,
inner epicanthal fold, deep set eyes, low set ears and
downslanting palpebrae. The clinical findings of our case
seem to be compatible with these findings [1].
Autism or autistic-like behavior has been commonly
described in individuals with idic(15) and thus an asso-
ciation between the syndrome and autism is suggested
[4]. However, standardized assessment for autism has not
been used in most studies of the syndrome. One study
attempted to elucidate the true relationship between
idic(15) and autism using a standardized assessment tool
in 29 individuals with the syndrome. Of these individuals,
20 had a high probability of being autistic and eight of the
nine remaining children were under five years of age. The
authors suggest that the onset of some autistic features
may, as such, be delayed [8]. Our subject did not show
any autism or autistic-like behavior up to 19 months, but
these findings indicate there is a possibility he may de-
velop autism and autistic behavior at a later point. The
natural history of this syndrome in relation to the devel-
opment of autism is a matter for future longitudinal stud-
ies to investigate.
Seizures represent an important medical feature of this
syndrome. Over 75% of sufferers have at least one seizure
and a wide variety of seizures may occur [4]. In our case,
a history of seizures had not occurred at 19 months, but
careful monitoring of future developments in this area is
warranted.
At the present time, there is no specific treatment that
can directly address the genetic changes in these individ-
uals. Symptomatic management associated with idic(15)
may be helpful to minimize the consequences of this ge-
netic syndrome.
In conclusion, idic(15) is considered as a clinically rec-
ognizable disorder. Clinicians should suspect this syn-
drome in any infant or child with early central hypotonia,
minor dysmorphic features, developmental delay/ID and
autism-like behaviors and who subsequently develops
hard to control seizures/epilepsy [4]. However, there is a
large phenotypic variability and thus it is not always pos-
sible to recognize this syndrome through only its clinical
features. Chromosomal analysis will be helpful in some
cases. Early identification of this syndrome may be use-
ful for providing appropriate and timely intervention
through careful attention to the development of seizure
and autism or autistic-like behavior. Our study provides
information as to the early clinical features of idic(15)
seen in our case and provides a literature review.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article
was reported.
REFERENCES
1. Battaglia A. The inv dup(15) or idic(15) syndrome: a
clinically recognisable neurogenetic disorder. Brain
Dev 2005;27:365-9.
2. Urraca N, Davis L, Cook EH Jr, Schanen NC, Reiter
Doug Ho Park, et al.
294
www.e-arm.org
LT. A single-tube quantitative high-resolution melt-
ing curve method for parent-of-origin determina-
tion of 15q duplications. Genet Test Mol Biomarkers
2010;14:571-6.
3. Hogart A, Wu D, LaSalle JM, Schanen NC. The comor-
bidity of autism with the genomic disorders of chro-
mosome 15q11.2-q13. Neurobiol Dis 2010;38:181-91.
4. Battaglia A. The inv dup(15) or idic(15) syndrome (tet-
rasomy 15q). Orphanet J Rare Dis 2008;3:30.
5. Buoni S, Sorrentino L, Farnetani MA, Pucci L, Fois
A. The syndrome of inv dup(15): clinical, electroen-
cephalographic, and imaging findings. J Child Neurol
2000;15:380-5.
6. Kwasnicka-Crawford DA, Roberts W, Scherer SW.
Characterization of an autism-associated segmental
maternal heterodisomy of the chromosome 15q11
—
13
region. J Autism Dev Disord 2007;37:694-702.
7. Robinson WP, Binkert F, Gine R, Vazquez C, Muller W,
Rosenkranz W, et al. Clinical and molecular analy-
sis of five inv dup(15) patients. Eur J Hum Genet
1993;1:37-50.
8. Rineer S, Finucane B, Simon EW. Autistic symptoms
among children and young adults with isodicentric
chromosome 15. Am J Med Genet 1998;81:428-33.
... 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. ...
... The genes that are maternally preferentially expressed in the PWACR area are specifically expressed in the brain, such as UBE3A and ATP10A. This area also contains bi-allelically expressed genes, such as GABA A receptor subunit genes (GABRB3, GABRA5, and GABRG3), which may be overexpressed in patients with idic(15) in whom they can cause clinical effects [34,35], including intellectual disabilities, autism and epilepsy [10,13,31,35,36]. In our study, we used DNA fingerprinting analysis to verify that the idic(15) of patient 1 was maternal. ...
Rare partial octosomy and hexasomy of 15q11-q13 associated with intellectual impairment and development delay: Report of two cases and review of literature
Article
Full-text available
  • Feb 2018
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.
View
... However, the youngest patient in their series was 9 yrs., so it is uncertain if microcephaly was acquired. A 9 months-old-boy with dup 15q11-q13 and microcephaly presented with delayed motor development, but had no abnormal clinical signs reported at birth, with a normal birth weight, and a normal brain MRI at 4 months of age (Park et al., 2013). This boy's microcephaly appears to have been acquired by 9 months of age. ...
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Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer’s Disease. We have reported high levels of Amyloid-β Precursor Protein (APP) and secreted APP-alpha (sAPP a ) and low levels of amyloid-beta (Aβ) peptides 1–40 and 1–42 (Aβ40, Aβ42) in plasma and brain tissue from children with ASD. A higher incidence of microcephaly (head circumference less than the 3 rd percentile) associates with ASD compared to head size in individuals with typical development. The role of Aβ peptides as contributors to acquired microcephaly in ASD is proposed. Aβ may lead to microcephaly via disruption of neurogenesis, elongation of the G1/S cell cycle, and arrested cell cycle promoting apoptosis. As the APP gene exists on Chromosome 21, excess Aβ peptides occur in Trisomy 21-T21 (Down’s Syndrome). Microcephaly and some forms of ASD associate with T21, and therefore potential mechanisms underlying these associations will be examined in this review. Aβ peptides’ role in other neurodevelopmental disorders that feature ASD and acquired microcephaly are reviewed, including dup 15q11.2-q13, Angelman and Rett syndrome.
View
... [2][3] 。sSMC 在普通人群的 发生率为 1/30 000 [4] ，中国人群中仅见数例报道 [5][6] CGH) 8×60 K 芯片(Agilent Technologies，美国) 进行比较基因组芯片杂交，按照说明书进行操 作。应用荧光素(cy3/cy5)标记患者和参照样本 的 DNA，然后进行芯片杂交和杂交后洗涤，荧 光 图 像 由 Agilent 芯 片 扫 描 仪 获 取， 应 用 Feature Extraction 软 件(Agilent Technologies) 读 取 数 据，并进行标准化处理。应用 Genomic Workbench (Agilent Technologies) 进 行 数 据 分 析， 发 现 拷 贝数改变区域。基因组中的位置判断根据 2009 年 2 月 UCSC 数据库提供的人类基因组参考序列 (GRCh37/hg19)。 基 因 相 关 的 临 床 信 息 通 过 在 线人类孟德尔遗传(OMIM, www.ncbi. nlm.nih.gov/ ...
A clinical and genetic analysis of a child with supernumerary marker chromosome 15-caused mental retardation, intractable epilepsy, and central precocious puberty
Article
Full-text available
  • Aug 2018
  • Chin J Contemp Pediatr
Supernumerary marker chromosome 15 is a rare chromosome abnormality. This paper reports the clinical diagnosis and treatment, as well as genetic defects, of a child with supernumerary marker chromosome 15. The patient was a 9.5-year-old girl who had mental and motor retardation since infancy, breast development at the age of 7 years, and seizures at the age of 8.5 years. Seizures occurred with various features and could not be controlled by a variety of antiepileptic drugs. No abnormalities were found by brain magnetic resonance imaging. Electroencephalogram showed frequent epileptiform discharges. G-banding karyotype analysis, fluorescence in situ hybridization, methylation-specific multiplex ligation-dependent probe amplification, and array comparative genomic hybridization identified a de novo 15q duplication in the patient. The maternal copy number increased in the 15q11-13 region. The form of genome rearrangement was 47,XX,+inv dup(15)(pter to q13:q13 to pter). The increased copy number in the 15q11-13 region is closely related to mental retardation, intractable epilepsy, and central precocious puberty. High-resolution karyotype analysis is recommended for children with unexplained mental retardation and epilepsy.
View
... In a review of the types and incidence of marker chromosomes at a university hospital in Korea, there was a report on a patient that presented idic(15) along with various other marker chromosomes [2]. Recently, two additional cases of idic(15) syndrome in Korea were published in reports focusing on their specific phenotypes [3,4]. We present a Korean patient with delayed development and café-au-lait spots, a novel associated phenotype, who was diagnosed with idic(15) syndrome. ...
View
... Chromosomal abnormalities that result in genomic imbalances are a major cause of congenital and developmental anomalies including multiple congenital malformations and mental retardation [1]. They can result from a numerical imbalance or from a structural change in the chromosomes resulting in partial deletions and/or duplications. ...
Clinical, Cytogenetic, and Biochemical Analyses of a Family with a t(3;13)(q26.2;p11.2): Further Delineation of 3q Duplication Syndrome
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  • Jan 2013
Chromosomal abnormalities that result in genomic imbalances are a major cause of congenital and developmental anomalies. Partial duplication of chromosome 3q syndrome is a well-described condition, and the phenotypic manifestations include a characteristic facies, microcephaly, hirsutism, synophrys, broad nasal bridge, congenital heart disease, genitourinary disorders, and mental retardation. Approximately 60%-75% of cases are derived from a balanced translocation. We describe a family with a pure typical partial trisomy 3q syndrome derived from a maternal balanced translocation t(3;13)(q26.2;p11.2). As the chromosomal rearrangement involves the short arm of an acrocentric chromosome, the phenotype corresponds to a pure trisomy 3q26.2-qter syndrome. There are 4 affected individuals and several carriers among three generations. The report of this family is relevant because there are few cases of pure duplication 3q syndrome reported, and the cases described here contribute to define the phenotype associated with the syndrome. Furthermore, we confirmed that the survival until adulthood is possible. This report also identified the presence of glycosaminoglycans in urine in this family, not related to the chromosomal abnormality or the phenotype.
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Acute lymphoblastic leukemia in a nine-year-old girl with isodicentric chromosome 15 syndrome
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  • May 2019
Isodicentric chromosome 15, also called idic(15), is a rare chromosomal abnormality resulting from inverted duplication of proximal 15q. It is associated with specific clinical findings such as early central hypotonia, developmental delay, cognitive dysfunction, autism spectrum disorders, and seizure. Herein we describe a case of a girl with idic(15) syndrome who developed acute lymphoblastic leukemia (ALL) at the age of 9 years. Our case suggests a possible correlation between idic(15) and ALL, and possible functional links between these two conditions.
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Organization of the human superior olivary complex in 15q duplication syndromes and autism spectrum disorders
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a number of behavioral and social features. Although the etiology of most cases of ASD is idiopathic, a significant number of cases can be attributed to genetic causes, such as chromosome 15q duplications [dup(15q)]. Recent neuropathological investigations have provided evidence for distinct patterns of heterotopias and dysplasias in ASD and subjects with both ASD and dup(15q). Individuals with ASD characteristically have hearing difficulties and we have previously demonstrated significant and consistent hypoplasia in a number of auditory brainstem nuclei in subjects with ASD. Herein, we compare results from a morphometric investigation of auditory brainstem nuclei in subjects with ASD, dup(15q) and controls. Our observations in subjects with ASD support our previous reports. However, in subjects with dup(15q), we find significantly fewer neurons and in many nuclei, neurons were significantly smaller than in ASD subjects. Finally, we find a notably higher incidence of ectopic neurons in dup(15q). These results suggest that in the brainstem, these neuropathological conditions may evolve from some of the same developmental errors but are distinguished on microscopic features. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
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A Single-Tube Quantitative High-Resolution Melting Curve Method for Parent-of-Origin Determination of 15q Duplications
Article
Full-text available
  • Aug 2010
  • GENET TEST MOL BIOMA
The most common chromosomal abnormalities associated with autism are 15q11-q13 duplications. Maternally derived or inherited duplications of 15q pose a substantial risk for an autism phenotype, while paternally derived duplications may be incompletely penetrant or result in other neurodevelopmental problems. Therefore, the determination of maternal versus paternal origin of this duplication is important for early intervention therapies and for appropriate genetic counseling to the families. We adapted a previous single-reaction tube assay (high-resolution melting curve analysis) to determine the parent of origin of 15q duplications in 28 interstitial duplication 15q samples, one family and two isodicentric subjects. Our method distinguished parent origin in 92% of the independent samples as well as in the familial inherited duplication and in the two isodicentric samples. This method accurately determines parental origin of the duplicated segment and measures the dosage of these alleles in the sample. In addition, it can be performed on samples where parental DNA is not available for microsatellite analysis. The development of this single-tube assay will make it easier for genetic testing laboratories to provide parent-of-origin information and will provide important information to clinical geneticists about autism risk in these individuals.
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The inv dup (15) or idic (15) syndrome (Tetrasomy 15q)
Article
Full-text available
  • Dec 2008
  • ORPHANET J RARE DIS
The inv dup(15) or idic(15) syndrome displays distinctive clinical findings represented by early central hypotonia, developmental delay and intellectual disability, epilepsy, and autistic behaviour. Incidence at birth is estimated at 1 in 30,000 with a sex ratio of almost 1:1. Developmental delay and intellectual disability affect all individuals with inv dup(15) and are usually moderate to profound. Expressive language is absent or very poor and often echolalic. Comprehension is very limited and contextual. Intention to communicate is absent or very limited. The distinct behavioral disorder shown by children and adolescents has been widely described as autistic or autistic-like. Epilepsy with a wide variety of seizure types can occur in these individuals, with onset between 6 months and 9 years. Various EEG abnormalities have been described. Muscle hypotonia is observed in almost all individuals, associated, in most of them, with joint hyperextensibility and drooling. Facial dysmorphic features are absent or subtle, and major malformations are rare. Feeding difficulties are reported in the newborn period. Chromosome region 15q11q13, known for its instability, is highly susceptible to clinically relevant genomic rearrangements, such as supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15. Inv dup(15) results in tetrasomy 15p and partial tetrasomy 15q. The large rearrangements, containing the Prader-Willi/Angelman syndrome critical region (PWS/ASCR), are responsible for the inv dup(15) or idic(15) syndrome. Diagnosis is achieved by standard cytogenetics and FISH analysis, using probes both from proximal chromosome 15 and from the PWS/ASCR. Microsatellite analysis on parental DNA or methylation analysis on the proband DNA, are also needed to detect the parent-of-origin of the inv dup(15) chromosome. Array CGH has been shown to provide a powerful approach for identifying and detecting the extent of the duplication. The possible occurrence of double supernumerary isodicentric chromosomes derived from chromosome 15, resulting in partial hexasomy of the maternally inherited PWS/ASCR, should be considered in the differential diagnosis. Large idic(15) are nearly always sporadic. Antenatal diagnosis is possible. Management of inv dup(15) includes a comprehensive neurophysiologic and developmental evaluation. Survival is not significantly reduced. The inv dup(15) or idic(15) syndrome can also be termed "tetrasomy 15q". About 160 patients have been reported in the medical literature [1-5].
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Characterization of an Autism-Associated Segmental Maternal Heterodisomy of the Chromosome 15q11–13 Region
Article
Full-text available
  • May 2007
Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome (PWS/AS) critical region have been described in individuals with autism. Maternal duplications and linkage disequilibrium in families with autism suggest the existence of a susceptibility locus at 15q11-q13. Here, we describe a 6-year-old girl diagnosed with autism, developmental delay, and delayed expressive and receptive language. The karyotype was designated de novo 47, XX, idic(15)(q13). Fluorescence in situ hybridization (FISH) and molecular analysis with 15q11-q13 markers revealed an additional copy of the region being of maternal origin. Duplication of the 15q11-q13 segment represents the most consistent known chromosomal abnormality reported in association with autism. This present case report reinforces the hypothesis that additional copies of this chromosome segment are causally related to autism.
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The Comorbidity of Autism with the Genomic Disorders of Chromosome 15q11.2-q13
Article
  • Oct 2008
  • NEUROBIOL DIS
A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.
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Clinical and Molecular Analysis of Five(Inv) Dup(15) Patients
Article
  • Feb 1993
Five patients with inv dup(15) chromosomes were investigated with molecular probes on proximal 15q to determine the parental origin and extent of the duplicated segment. Cytogenetic investigation showed that four patients carried one and a fifth patient had two extra chromosomes derived from number 15 in all cells. In situ hybridization with a chromosome 15 library and a centromere 15 probe confirmed that the entire inv dup chromosomes were derived from chromosome 15. Molecular analysis using probes mapping in the region deleted in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients implied that in at least two patients the extra chromosomes were asymmetric with one copy of the PWS region on the extra marker chromosome but two copies of the region centromeric to the PWS region. Three other cases had an inv dup(15) with two extra copies of the PWS region, but in one of these, heteromorphisms clearly demonstrated that the two centromeres derived from two different chromosomes. The inv dup(15) presumably resulted from an illegitimate recombination event between two different chromosomes 15 in most or all of these cases. All patients showed a maternal origin of the duplicated chromosome. The clinical severity appears to be associated with dosage of the PWS/AS region rather than with differences in the extent of the duplicated segment.
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Autistic symptoms among children and young adults with isodicentric chromosome 15
Article
  • Sep 1998
A standardized assessment of autistic symptomatology was completed for 29 children and young adults with a supernumerary isodicentric chromosome 15 (formerly known as inverted duplication 15). Although there was variability in severity, 20 individuals with an isodicentric chromosome 15 [idic(15)] had a high probability of being autistic. Eight of the 9 remaining children were under age 5 years and were more sociable than the rest of the cohort. Group characteristics such as gender and seizure presence could not explain the observed difference between older and younger individuals in our study. The natural history of isodicentric 15 syndrome remains to be shown through longitudinal work and may include an age-related risk for developing autism.
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The Syndrome of Inv Dup (15): Clinical, Electroencephalographic, and Imaging Findings
Article
  • Jul 2000
The clinical and laboratory data of four pediatric patients and one adult patient with inverted duplication (inv dup) (15) are reported. The most evident findings were dysmorphic features with frontal bossing; genital abnormalities, such as macropenis or hypospadias; mental retardation; autistic behavior; and seizures. Two additional adults with inv dup (15) from other institutions were also diagnosed in our laboratory. Seizures and mental retardation were the reasons for their referral. The clinical picture of inv dup (15) seems to be quite variable since the phenotype can also be normal. However, karyotyping and fluorescent in-situ hybridization, focused in particular on chromosome 15, appear to be indicated in patients with dysmorphic phenotypes, such as the one present in our patients, and in subjects with early-onset seizures and psychomotor retardation with autistic features.
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The inv dup(15) or idic(15) syndrome: A clinically recognisable neurogenetic disorder
Article
  • Sep 2005
  • BRAIN DEV-JPN
The chromosome region 15q11q13 is known for its instability, and many rearrangements may occur in this imprinted segment: deletions associated either with Angelman syndrome (AS) or with Prader-Willi syndrome (PWS), according to parental origin; translocations; inversions; and supernumerary marker chromosomes formed by the inverted duplication of proximal chromosome 15. Inv dup(15) constitute the most common of the heterogeneous group of the extra structurally abnormal chromosomes, and their presence results in tetrasomy 15p and partial tetrasomy 15q. Inv dup(15), containing the Prader-Willi/Angelman syndrome region, are associated with altered behaviour, developmental delay/mental retardation, and seizures/epilepsy. Clinicians should suspect this syndrome in any infant/child with early central hypotonia, minor dysmorphic features, developmental delay, autism or autistic-like behaviour, and who subsequently develops hard to control seizures/epilepsy. Diagnosis is confirmed by standard cytogenetic techniques and FISH analysis. Although, about 100 cases have been reported to date, limited data are available on the natural history. To obtain better information on diagnosis and outcome in a clinical setting, we reviewed the available literature on clinical and behavioural phenotype of inv dup(15) syndrome.
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