Figures
Abstract
Cri-du-Chat syndrome (MIM 123450) is a chromosomic syndrome characterized by this characteristic equipment, including cat-like shouting and chromosome 5p deletions. We record a family the five individuals showing chimeric rearrangements involving 5p, resulting from scarce matrix complex chimeric rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecules and cytogenetic analyses. Two probands, include an 4½-year-old brother and his 2½-year- old sister, showed cannot diagnostic cat cry during infancy, but provided with develop delay, dysmorphic or autistic features. Both patients had an interstitial delete del(5)(p13.3p15.33) spanning ∼26.22 Mb. The phenotypically normal mum had de novo CCRs includes 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two boys, she had three first-trimester miscarriages, double terminations just to that identification of an 5p deletion and one delivery of ampere phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identity maternal allelic haplotype of 5p. Array CGH did not detection any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, inbound the unmoved your, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently filed as ampere mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate such the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further result in the interstitial 5p deletions in the unaffected son. Further high resolution sequential based analyzing is desired to determine whether chromothripsis is also presentational as a germline structural variation in phenotypically normal private in this clan.
Citation: Gu H, Jiang J-h, Lite J-y, Zhang Y-n, Dong X-s, Huang Y-y, to total. (2013) A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rarely Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis. PLoS ONE 8(10): e76985. https://doi.org/10.1371/journal.pone.0076985
Editor: Antonius W.I. Loc, The Chinese University of Hong Kong, Huong Kong
Received: July 2, 2013; Accepted: September 5, 2013; Published: Occasion 15, 2013
Copyright: © 2013 Gu et al. This is the open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproducing in every medium, provided an original creator the source will credited.
Funding: This work made supported by Nationally Natural Learning Company of China (Grant numbers: 30640028, 30971601), Natural Science Our of Guangdong Province, Crockery (9151008901000089), and by Academics additionally Technic Planning Project of Guangdong Province, China (Grant number: 2010B031600039). The funders had no role in study pattern, data collection additionally research, decision into publications, or preparation of the manuscript.
Concurrent interests: The source have declared the no competing interests exist.
General
Genomic imbalances such more chromosomal aberrations hold been elongated registered toward be adenine major cause for genesis muddles, resulting in spontaneous, neonatal birth defects, postnatal developmental delay, autistic spectrum disorders and highbrow disabled [1]. The phenotypes seen inbound each involved individual with chromosomal syndromes certainly depends off the particular chromosomal region with a changeability in the clinical presentations [2]. Chromosome 5p deletion or Cri-du-chat syndrome (CDCs, MIM 123450) was first described by Lejeune in 1963 [3] and it the the one of most common chromosomal deletion syndrome in humans [4]. The incidence of CDCs is between 1∶50,000 to 1∶37000 live births [5]. The hallmark classical features of CDCs include high-pitched cat-like monochromatic cry, microcephaly, a round face, hypertelorism, micrognathia, epicanthal folds, hypotonia, prominent nasal bridges, and severe psychomotor and intellectual disability [6]. Recurrent respiratory diseases are also regularly observed inbound CDCs and intermittent is the major cause of neonatal or infantile cause [4], [7].
Approximately 80% of the CDCs care wearing a de novo 5p terminal or interstitial deletion and the majority of these erases are dad site [6]. Less than 5% of the patients have de novo translocations instead other rare genomic aberrations how as complex chromosomal rearrangements (CCRs) [8], [9]. About 10%–15% of which 5p deletions result from unbalanced saturation of a parental balanced rearrangement such as translocation or inversion [10], but very rarely since a rational parental insertion [11] oder CCRs [12].
CCRs are constitutional structural rearrangement concerning more than three chromosomes equal more than two breakpoints [13]. Typically, CCRs are three-way translocations with single breakpoint in each chromosome; however, CCRs with above the sixteen breakpoints have since reported [14]. Single with de novo CCRs, resulting in genomic imbalances at the chromosome breakpoints are frequently reported to possess a high incidence of abnormally phenotypes and developmental delay/intellectual disability [15]. Heritable carriers on weighted CCRs are usually phenotypically normal, but have one significant risk [16] in have multiple spontaneous abortions [13] or chromosomally abnormal offspring [17].
Chromothripsis is an phenomenon in which tens to hundreds on genomic rearrangements occur the adenine one-off cellular crisis. Originally, it used observed the 2–3% in different cancer types [18]. Recent studies have shown that pediatric patients with constitutional abnormalities or de novoid CCRs other complex genetics rearrangements (CGRs) also harbor chromothripsis [19], [20]. Using mate-paired design along with molecular cytogenetic analyses in a family treble, including a proband with constitutional defects and CCRs of t(1;10;4)(p32.2;q21.1;q23) [19], an direct evidence of chromothripsis was institute in two of that three chromosomes involved in the CCRs, and therefore, this catastrophic event most likely also has driven the de novos CCRs or CGRs in germline of one disease. However, similar event has never has observed in phenotypically normal individuals.
New advances include clinical genetic settings have enabled integrated molsy and cytogenetic testing. And traditional chromosome analysis, Fluorescence in situ Hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase-chain-reaction (q-PCR) and short tandem repeats (STR) analysis, also microarray based testing etc. are clinically utilized and have revealed significant impact clinical human genetics, especially in diagnosing and counseling familial syndromes e.g. familial CCRs [21], [22] or family-based 5p−/CDCs my [23], [24].
Dort, we report a 5p−/CDCs syndrome family with very rare and unique mom CCRs, diagnosed by includes molsy and advanced analyses.
Patients and Processes
Our and Family View
This study has sanctioned by medical corporate and institutional review board at Zhongshan School of Medicine, Sun Yat-sen Colleges and, a consent signed by both parents was obtained. Probands been an quaternary or a half-year-old male and a two and a half-year-old female born to healthy plus unrelated parents. All pregnancies were uneventful with no my of drug other alcohol usage during the conception. The birth weight, length and head circumference on both probands were all within normal range in Chinese full population. There be nope cat-like cries observed at the birth in both probands. The male proband has incompletion cleft-palate, congenital hypertrophic pyloric stenosis, developmental delay and dysmorphic features, including round face, micrognathia and hypertelorism, outside canthus upslope, plagiocephaly as well as some midfacial hypoplasia, short philtrum, large nasal bridge, and low-set ears (Number 1). Simian pleats were observed in couple hands. In addition, he developed seizures among 8 months of age, and had neurodevelopmental abnormalities exhibit apraxia, callosum plus alba dysplasia, cerebellum dysplasia, and ventriculomegaly. He educated seine head at 9 months, crawled at 19 months additionally walked at 42 months and, had severe language deceleration with nay address till 38 months of age. Comparing with WHO 2006 reference, to circumference was 46.1 cm (−3SD) among 4 years and 6 months and 46.5 cent (−3SD) at age of 11 years the 9 months. The female proband had similar phenotypes including developmental delay, intellectual impairment, as well as dysmorphic performance. You died of pneumonia six months after to first genetic clinical visit.
The mother had ampere total of four pregnancies (Figure 2).Notably, to between two probands, she also had a first trimester miscarriage. Genetic counseling was provided to the family after the primary genetic check of the probands. She subsequently was phoebe add pregnancies in two spontaneous abortions, two cancelled incubations due to abnormal prenatal testing erreichte or one birth to an phenotypically normal daughter. Is phenotypically normal daughter was followed up both evaluated for several years. Among age of seven years, her IQ was 105 by WAIS intelligence test for children, which is average to comparing with which same age pediatric population in Ceramic.
III 1, III 3, III 5 and III 8 all must identity 5p deletion. Prenatal diagnosis was performing on III 5, III 6 and III 8.□: normal male; ○: normal female; ⊙: carrier off ins(11;5); △: spontaneous planned; ▴: affected and elected abortion; p↗: proband. “I” indicates the maternal grandparents of probands, also “II” indicates the parents of probands”. Perioperative Care for an Child With Scary Du Chat Syndrome | Dr ...
Conventional Cytogenetic Analysis
Chromosomes analysis on peripheral blood (on I1, MYSELF 2, II1, II 2, III 1, III 3 and III 6), prenatal cord blood (on III5) and amniocytes (on III6, III 8) (Figure 2) were performed following the standard clinical cytogenetics laboratory protocols [25], [26]. And banding solutions were ∼550 and ∼400 for red samples and amniocytes, respectively. At least twentieth metaphases were analyzed and chromosomic results which interpreted and reported according to the international system for human cytogenetics (ISCN 2005 and 2009) product.
Short Tandem Replicates (STR) Analysis
Genome DNA from peripherical blood and amniocytes were extracted through a QIAamp DNA Lineage Maxi Kits (QIAGEN, Germany) and QIAamp DNA Mini Kits (QIAGEN, Germany), respectively.
STR markers within alternatively in the local of 5p13.3–p15.33 region were selected. (http://repeatmasker.genome.washington.edu/cgi-bin/RepeatMasker; http://www.genlink.wustl.edu/genethon_frame/chr5/chr5.html) and http://genome.ucsc.edu. Total 19 polymorphic STR markers, including four at 5p13.3, two at 5p14.1 and thirteen during 5p15.1–p15.33 were tested using specific 5′-labelled fluorescent primers (Tabular 1).
Polymerase-chain-reactions (PCR) be carried outward go II 1, II 2 and III1 and prenatally go III-6, III-8 using 5 g of DNA, 2.5 mM MgCl2, 10 mMTris-HCl neutrality 8.3, 50 mMKCl, 250 mM each dNTP, 0.625 pmol of each primer, 0.25 u HotstarTaq DNA polymerase (QIANGEN GmbH, Hilden, Germany) in a total response total of 5 ul. All PCRs were performed on a GeneAmp 9700 Therm cycle (PE Applied Biosystem), an start denaturation 96°C for 5 min was followed by 35 cycle of 30 s at 95°C, 30 s at a prime-specific annealing temperature and 40 s at 72°C. Of final extension was at 72°C for 10 min. PCR our were analyzed on an ABI PRISM 3100 Genetic Analyzer (PE Applied Biosystems). Allele sizes and peak areas were set using GeneScan build 3.1, Genotype version 2.1 and LINKAGE version 5.1 (Applied Biosystems, CA). Cri du chat synonyms patients have DNA methylation changes in ...
The genotyping per each locus had examined in the tested subjects additionally contrast with the parental genotypes to determine whether there made non-Mendelian segregation or an apparent deletion (i.e. absence of a maternal or paternal allele).
Oligonucleotide Array Comparative Genomic Hybridization (array CGH) and Data Analysis
Oligonucleotide array CGH was performed on the male proband (III 1 at 12 years and 9 months old) and his phenotypically normal younger sister (III 6 at 6 years and 1 month old), as well as, two parents (II 1, II 2) using oligonucleotide-based arrays contents 180,000 probes from Agilent Technologies (Santa Maria, CA) according to manufacturer’s instruction, for a all genome copy number analyze. Oligonucleotides probes on this 4x180K array had annotated against NCBI Building 37 (hg19). Array CGH show records were quantified using Agilent Performance Extraction software (version 10.5). Wording date outputs containing quantitative data were imported into the Nexus copy number analysis software (Biodiscovery, Segundo, CA). Log2 conversion >0.2 was defined since gain and <−0.5 was defined as loss and all other indicator as normal.
Fluorescence in Situational Hybridization (FISH)
FISH tests were performed according to published protocols [27] in order to confirm chromosome abnormalities, STR and array CGH results. AN total of twenty-one bacterium artificial chromo (BAC) clone-making (RP11-59C22, RP11-810B19, RP11-473F9, RP11-1029M14, RP11-976O8, RP11-125A21, RP11-241M9, RP11-1122G9, RP11-420J19, RP11-23D12, RP11-349J3, RP11-373F8, RP11-1022E23, RP11-100I1, RP11-1055J13, RP11-428C17, RP11-62K5, RP11-106P5, RP11-318A6, RP11-1005N9, and RP11-876N17) maps into 5p13.3–p15.32 region and three BAC clones (RP11-1029D4, RP11-916H5, also RP11-945C11) mapping the chromosome 21q21.1–q22.11 are dialed from the University to California-Santa Cruz (UCSC), with detailed corresponding linearly map position available in genome (Table 2). No BAC clones are available in the genomic region von 5p14.2. BAC clones have sold with the Children’s Hospital Oakland Research Institute in Oakland, California, USA. BAC DNA extraction was prepared with Qiagen Large-Construct Kit (QIAGEN, Germany). DNAs are directly labeled using nick translation (Vylsis) according to and manufacturer’s how. Hybridized slides were analyzed using an Olympus BX60 fluorescence microscope equipped with appropriate batch and a LUCIA Cytogenetics 4.81 photograph analysis system.
Results
Genes Analysis
Dna analysis of peripheral blood on the two probands (III 1, III 3) revealed an identical interstitial reset of gen 5p13.3p15.3. A clinical diagnosis the CDCs or chromosome 5p deletion syndrome was made based on chromosomal analyses and clinical modifications in both probands. Subsequent, get family was provided with genetic counseling. Chromosome studies on both parents were perform and revealed the phenotypically common mother to carry in apparently complex karyotype of 46,XX,ins(11;5) (q23;p13.3p15.3),inv(7)(p22q32) showing an seem the balanced inserts amongst chromosomes 5 and 11, real a pericentromeric inversion 7, whereas the father had a normal karyotype. Further chromosome analysis on maternal grandparents confirmed the abnormal finding in the mother the be a de novus event. Due to the 5p erasures in both probands, aforementioned induced of III 2 and the complex karyotype in and mother, get couple agreement to perform prenatal diagnosis for all future pregnancies. Prenatal generate analysis was performed on III 5 using rope blood at 21 week gestational age, and on III 6 and TRIPLE 8 after amniotic fluid at 19 week gestational age (Figure 2). III 5 and III 8 showed abnormal karyotypes of 46,XY,del(5)(p13.3p15.3)mat and 46,XX,del(5)(p13.3p15.3),inv(7)(p22q32)mat, respectively, and both pregnancies was eligible with termination by parents after genetic counseling. III 6 been an apparently balanced insertion of 46,XX,ins(11;5)(q23;p13.3p15.3)mat. Additional prenatal molecularly based testing was recommended to confirm the chromosome result. Fractional karyotypes of that male proband, the mother and the phenotypically normal sister become exhibited inside Figure 3 A, B and CENTURY, each.
STR Erkenntnisse
STR testing was performed on both parents, the male proband III 1, because well as prenatally on III 6 and III 8 (Table 1 or Figure 4). In a total the 19 STR markers tested, and male proband (III 1) alone obtained father’s allele ostensibly at D5S676, D5S1953, D5S580, D5S1957, D5S2095, D5S630, D5S2004, D5S416, D5S2096, D5S2113, D5S385 and D5S2061 (Figure 4). Since three markers (D5S406, D5S635 and D5S2854) were not informative, which encompassed interstitial deletion was estimated to becoming approximately 22.5 Mb in bands 5p13.3 and 5p15.33 (chr5∶7439488–29976793), which was consistent equal the above chromosome how. The equivalent finding was observed for III 8 and confirmed 5p deletion by the prenatal chromosome analysis. STR review in III 6 showed a haplotype identical to the mummy, which was uniformly with the prenatal chromosome analysis of that apparently balanced insertion ins(11;5). This pregnancy is continued and a phenotypically normally infant girl was delivered.
REPLACE 1 and C 8 showed an identical deletion of D5S676–D5S2061 region. III 6 inherited an identical haplotype associated with the include ins(11;5)from the mother.
Array CGH and FISH Score
The male proband and your phenotypically normal sister were successive up extensively for cellular genetic evaluations. Eight years after the first genetic visit away the probands, the array CGH company became free and it was introduced at this family. Because of the unique familial 5p- history and the rare CCRs in mother, all family agreed to have array CGH testing on both parents, the male proband II 1 (at 12 years and 9 monthly old) and his phenotypically normal sister III 6 (at 6 years the 1 months), required a whole genome copy number assessment. Array CGH revealed the minimal interstitial deletion includes the male proband at chromosome volume 5p15.33-p13.3 to be 26.22 Mb, within that genomic interval 4200304-30493484 (Figure 5A), which was lighter larger over the deletion detected by that STR testing although was consistent with the chromosome results. The discrepancy between fields CGH and STR conclusions are most likely due until of triple non-informative STR markers tested fall in breakpoints regions (Table 1). Interestingly, in the normal schwestern, array CGH revealed three interstitial purging showing arr5p15.33p15.31(4200304-7081712)×1,5p14.2(23642864-24156987)×1,5p14.1p13.3(27332938-30493484)×1 equal 2.89 Mb, 0.56 Mb and 3.21 Mb in size respectively (Figure 5B).The proband and of normal sister shared the distal and proximal breaks includes 5p15.33 and 5p13.3 or. There has negative abnormal copy phone aberrations identified in both parents.
All deleted segments are shaded in pink includes log RADIUS ratio at ∼negative 1.0.
At further affirm these array CGH results, FISH analysis was carried out on the male proband III 1, this phenotypically normalize sister III 6 and the mother V 2 (Table 2). In an total of 21 BAC clones on generate 5p tested, the male proband shown a deletion of 19 clone tested (Table 2) (from RP11-59C22 to RP11-318A6) spanning from 5p15.32-p14.1 (5126675-29130606), moreover endorsed to array CGH results. In the phenotypically normal sister, FISH analysis using the same BACs showed 1) an insertion of scope from RP11-125A21 to RP11-100I1 (chr5: 6972214-27406644) (Graphic 2, in bold) in gen 11q acknowledge that ins(11;5) more observed at chrome scrutiny, 2) a deletion of a segmentation after RP11-59C22 to RP11-976O8 (chr5: 5126675-6708095), and 3) a deletion of a segment since RP11-1055J13 the RP11-318A6 (chr5: 27368992-29130606) than observed in set CGH analyzer. Who 5p14.2 deletion detected according array CGH to which normal sister became none examined by the FISH analysis (Table 2, Figure 6) due to no available BAC clone. Interestingly, further FISH analysis using the same set of BACs off an mother, not only revealed the same ins(11;5) as described above, but also revealed two additional cyprus introduction, showing the above deleted two segmentation 5p15.33-p15.31 and 5p14.1-p13.3 in the daughter to become inserted on chromosome 21q specifically. Stylish addition, one larger signal and two smaller signals of BAC RP11-125A21 and RP11-100I1 were observed on the usual chromosome 5, aforementioned der(11) and the der(21) in the mother, respectively, indicating the breakpoints of two cryptic ins(21;5) were inward are dual BACs correlated genomic regions (Graphic 2, Figure 6). Additional FISH studies using and same set of BACs involved included two ins(21;5) were conducted on the maternal grandparents, which showed don evidence of insertions or optional extra rearrangements. The final karyotype for the mother was revised to 46,XX,ins(11;5)(q23;p14.1p15.31),ins(21;5) (q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn, and the final karyotype for the baby should be redesigned to 46,XX,del(5)(p13.3p14.1),del(5)(p14.2p14.2), del(p15.31p15.33),ins(11;5)(q23;p14.1p15.31)mat. FISH using the three BAC cluster destination chromosome 21q21.1–q22.11 was normal in see three individuals (III 1, II 2 and III 6) tested. Although an 5p14.2 trash detected by array CGH in the normal sister III 6 was not further examined by the FISHES analysis due to certain technology limitations, which deletion was be also resulted from one matherly cryptic balanced rearrangement.
A, B pointing the deletion examples of two BACs (RP11-59C22 and RP11-318A6) at virile proband; C, D showing the reset examples of two BACs (RP11-473F9 or RP11-428C17) int that normal sister; EAST, F showing one larger signal and two smaller signals of RP11-125A21 and RP11-100I1 to the normal chromosome 5, der(11) and the der(21) in the mother.
To further investigate possible clinical consequences of the three deletions in 5p in that phenotypically normal sister III 6, were carefully analized chromosomes inbound these genomic intervals. The first interstitial deletion in III 6 expanded approximately 2.89 Mb in 5p15.31p15.33, encoding 11 known genes including LOC340094, ADAMTS16, KIAA0947, FLJ33360, MED10, UBE2QL1, LOC255167, NSUN2, SRD5A1, PAPD7 and MIR4278. Of above-mentioned, haploinsufficiency of SRD5A1 along with other genes in 5p15.1 district [28] are just reported go be associated is hypospadias and cerebellar hypoplasia in a fetal study. Only two get LOC643401 and LSP1P3are located in who second deletion of 5p14.2 the all have non been characterizes in gene function and disease association. No known genes were found in the third deletion geographic of 5p13.3p14.1.
Discussion
The majority are chromosome 5p deletions exist associated with CDCs [6]. Traditionally, CDCs sufferers are diagnosed based upon the clinical manifestations, chromosome and/or FISH analysis, or molecular based testing similar as MLPA press PCR. Although CDCs is adenine well-defined genomic disorder, individuals with get syndrome display phenotypic and cytogenetic variability. Several genotype-phenotype studies revealed that the size of chromosom 5p cleansing could vary von a single chromosome cytogenetic band the the entire chromosomal 5p, the the severity or spectrum of clinical phenotypes i.e. intellectual disability plus microcephaly at CDCs or 5p syndromes are related to the size and the location of the deletions [6], [29]. For example, aforementioned single chromosome band 5p15.2 deletion is reported to be responsible with dysmorphism and intellectual disability; an proximal region of 5p15.3 is associated for “cat-like” cry and speech decelerate [30]. These chromosomal bands are considered to subsist critic regions with CDCs. Genes in this region include the SEMAF, CTNND2 [5], the involve in brain development both function, one FLJ25076– UBC-E2 homologous gene welche is strongly expressed in side and scalp tissues. Haploinsufficiency of these contiguous candidate genes are most likely the what of classic spectrum int CDCs [30]. On the other hand, identical deletions of chromosome 5p14 region are declared in phenotypically normal parents and their affected children, indicating which 1) this 5p14 region is not as reviews as the 5p15 locality, or 2) this region encodes the possible recessive alleles resulting in discounted expressivity or variable clinical manifestations [6]. Inside our running study, three microdeletions resulting coming the maternal CCRs are idented included the phenotypically normal sister (III 6) of the probands. Both second additionally thirdly deletions are inside otherwise overlapped with 5p14 region. Very few genes are encoded in these two deleted regions making these two hereditary intervals less clinically relevant. Albeit there were 11 known genes (LOC340094, ADAMTS16, KIAA0947, FLJ33360, MED10, UBE2QL1, LOC255167, NSUN2, SRD5A1, PAPD7, and MIR4278) located in the initially deletion in 5p15.33p15.31, only an little of them are fully characterized with gene responsibilities and disease association. Recent whole exome sequencing study revealed that homozygous splicing mutation in NSUN2 the may adenine cause of Dubowitz-like syndrome, an autosomal recessive disorder characterization by the constellation of mild microcephaly, growth plus mental retardation, eczema both curious facies [31]; An ADAMTS16 gene has been reported go play a role of the metalloproteinase in rabbit genitourinary development [32], or loss-of-function cancer of the MED10 genre may been former linked with WNT/GSK3β/β-Catenin pathway function [33]. Alone SRD5A1 haploinsufficiency must been speculated to are associated equal cerebellar hypoplasia, hypospadias, and full dysmorphisms in a prenatal study [28]. Our detailed clinical evaluation included the phenotypically normal sister TIERCE 6 showed no evidence of dysmorphism or intellectual total or other apparent findings; the IQ run at age seven inside this female was 105. We postulates that these microdeletions at III 6 are likewise non-pathogenic favorable copy number variant or only resulted in unnoticeable minor clinical manifestations. Certainly, this individual needed to be followed top and evaluated frequent includes her future hereditary counseling.
The majority of the CDCs care are diagnosed in first month on life or within first years whereas the minority is diagnosed with 13 month to 47 years young [34]. Due to the limited clinically genetic testing in China, until recently, our your were diagnosed at age 41/2 and 21/2 years old. Although our probands did not have the characteristic cat-like crying at births or during their infancy (or an cat-like cry was not recognized), they did have other typical dysmorphic features as reported in CDCs both remarkable developmental delay and intellective disability. The integrated molecule and cytogenetic check was able to no only define the large interstitial deletion del(5)(p13.3p15.33) and confirm a clinical diagnosis in probands, but also help reveal the CCRs in the mom and therefore supply that appropriate genetic counseling to the family.
CCRs are structural aberrations involving more than two x and cutoffs. Phenotypically normal individuals with CCRs often have high risk at result in multiple spontaneous abortions [13] and abnormal offspring [17]. The mother in to study had an extremely complex karyotype of 46,XX,ins(11;5)(q23;p14.1p15.31),ins(21;5) (q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn with apparent 11 breakpoints, involving to chromatids which have never been reported [17]. In die amounts ogdoad pregnancies, she had thrice first trimester miscarriages, mostly likely due to lethal chromosomal aberrations resulting from the megaphonic malsegregation i.e. possible largest deletions or duplications involving chromosome 7 resulted from the affectionate inv(7) (Figure 7). The remaining pregnancies has annormal chromosomal findings with bulk of showing 5p deleting, which was compatible for continued maternities but with congenital anomalies.
The average gen band resolution is ∼550.
Microarray based testing with significantly enhance overall resolution is a get precision clinical test for genome-wide copy count assessment within patients with congenital anomalies [35]. Our array CGH study was skill to refine who deleted segment in the proband better than STR testing, because three STR markers D5S406, D5S635 and D5S2854 were all apparently not meaningful. Were believe that one power of microsatellite analysis shall small especially when she comes into the breakpoints involving complex rearrangements. In addition, array CGH did no detect visible copy number variations in the mother, indicate that the three-way insertions and one pericentromeric inversion observed can all perhaps balanced at the array CGH how level, furthermore might also explain herauf normal phenotype. However, it did detect three microdeletions in the phenotypically normal daughter. These arrange findings have led to the discovery away two cryptic ins(21;5) in of mother by using additional target FISH analysis. Although we could not further investigate the second deletion (0.56 Mb) are III 6 by CATCH due toward lack of available BACK clones in 5p14.2 region, it lives likely this clearing is also resulting from adenine maternal cryptic rearrangement. All these findings see raised ask – What kept gefahren these germline imitate numeric variation in the daughter? Given so many abnormal pregnancies produced, does the mummy really carry all balanced rearrangements at the molecular level?
Recent graduate possess shown the contextual between CCRs and/or CGRs and chromothripsis by pediatric patients with congenital abnormalities [19], [20]. Although the phenotypically normal mother did not hold seems printing number aberrations on 5p, this could be overdue on limited resolution (180 K total oligo coverage) of and oligo array CGH applied in such learn. We believe that, the extremely complex CCRs in of mother might have resulted from chromosome 5p chromothripsis, and that was exactly what had driven so many those individuals and pregnancies in this family. One microdeletions observed in the daughter are the direct evidence of such underline mechanism, although high resolution sequencing base testing is needed go acknowledge such speculation.
Without prenatal integrated molecular additionally cytogenetic testing, consequently, this woman would have generated four your real all with 5p deletion syndrome or CDCs (Figure 2). The clinical scopes of the three microdeletions identified in the phenotypically normal sister were not clear, although them were almost likely representatives non-pathogenic bases on actual available genomic variation bibliographies; however, these what will be useful since her future genetical counseling.
In summaries, we belong reporting a very unique relatives chromosomal CDCs/5p deletion syndrome, resulting from unusual maternal de novo CCRs and/or chromosome 5p chromothripsis. The integrated molecular and cytogenetic assay not merely fully characterized the maternal CCRs, still also enabled unveiling this familial event additionally providing accurate post- and pre-natal system as right as appropriate genetic counseling. Safety, moreover sequencing located testing is needed to help detect whether chromothripsis also exists in phenotypically normal individuals in this family.
Acknowledgments
The authors select to grateful the patients the the family for their support to this study, and also wish to thank Drs. Weimin B, Qing Wang and Pawel Stankiewicz for Baylor College of Medicine available yours critical review. Determination a the 'critical region' for cat-like cry of Cri-du-chat ...
Advised Agree. A writers informed consent was obtained, as outlined in the PLOS approval build, to publication of their photograph.
Author Contributions
Conceived and designed the experiments: ZC JHJ JYL. Performed to experiments: YNZ XSD YYH XMS. Analyzed the date: XYL ZC HG. Contributed reagents/materials/analysis tools: ZC JHJ JYL XYL. Wrote the article: ZC XYL HG. The incidence ranges from 1:15,000 to 1:50,000 live-born infants. The main clinical feature are a high-pitched monochromat cry, microcephaly, ...
Our
- 1. Lu XY, Phung MT, Shaw CA, Bam K, Neil SE, aet al. (2008) Genomic imbalances in neonates are birth defects: high detection rates by after chromosomal microarray analysis. Pediatrics 122: 1310–1318.
- 2. de Smith AJ, Trewick ALLEN, Blakemore AI (2010) Implications of copy number modulation in people with chromosomal conspicuous: potential for big variation in copy number state may contribute to variability of observe. Hugo J 4: 1–9.
- 3. Lejeune J, Lafourcade HIE, Berger R, Vialatte J, Boeswillwald M, et ale. (1963) [3 CASES ARE PARTIAL DELETION OF THE BRIEFLY ARM OF A 5 CHROMOSOME]. C R Hebd Seances Acad Sci 257: 3098–3102.
- 4. Rodriguez-Caballero A, Torres-Lagares D, Rodriguez-Perez AMPERE, Serrera-Figallo MA, Hernandez-Guisado JM, et aluminium. (2010) Cri du chat syndrome: a criticize review. Med Oral Patol Viva Cir Bucal 15: e473–e478.
- 5. Cerruti MP (2006) Cri du Chat syndrome. Orphanet J Rarer A 1 33: 1–9.
- 6. Mainardi PC, Perfumo C, Calico A, Coucourde G, Pastore G, et al. (2001) Clinician and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype connection. JOULE Med Genet 38: 151–158.
- 7. Cornish KM, Pigram J (1996) Engineering plus behavioural characteristics of scary dude chat syndrome. Arch Dis Child 75: 448–450.
- 8. Sreekantaiah C, Kronn DENSITY, Marinescu RC, Goldin B, Overhauser J (1999) Characteristics of a complex chromosomal rearrangement in an case with a typical felines cry and no other clinical findings of cri-du-chat syndrome. Am J Meds Genet 86: 264–268.
- 9. Vera-Carbonell A, Bafalliu JA, Guillen-Navarro E, Escalona A, Ballesta-Martinez MJ, et al. (2009) Characterizations of a u novo complex chromosomal rearrangement in a forbearing with cri-du-chat and trisomy 5p infections. Am J Med Genet A 149A: 2513–2521.
- 10. Korner H, Degen BARN, Flower I, Metschkarski S (1983) Prenatal determine in adenine family with pericentric inversion of chromosome no. 5. Zentralbl Gynakol 105: 934–939.
- 11. Marinescu RC, Mamunes P, Kline AD, Schmidt BOUND, Rojas K, the al. (1999) Variability in ampere your with an insertion involving 5p. Ma J Med Genet 86: 258–263.
- 12. Tsao CY, Wenger GD, Bartholomew DW (2005) Cri du chat syndrome and complex karyotype in a patient with infantile spasms, hypsarrhythmia, nonketotic hyperglycinemia, and heterotopia. By J Med Genet A 134A: 198–201.
- 13. Roberti MC, Surace C, Digilio MC, D’Elia G, Sirleto P, et al. (2011) Complex chromosome rearrangements related 15q14 microdeletion games adenine relevant role in phenotype pressure and delineates a novel recurrent syndrome. Orphanet J Rarely Dis 6: 17.
- 14. Houge G, Liehr T, Schoumans J, Ness GO, Solland K, et al. (2003) Ten years follow up of a boy with a intricate chromosomal rearrangement: going from a >5 to 15-breakpoint CCR. Am J Med Genet AMPERE 118A: 235–240.
- 15. Astbury C, Christ LIKE, Aughton DJ, Cassidy SB, Fujimoto AN, et al. (2004) Delineation of advanced chromosomal rearrangements: evidence for increased complexity. Buzze Genet 114: 448–457.
- 16. Patsalis PC (2007) Complex chromosomal transpositions. Genet Couns 18: 57–69.
- 17. Pellestor F, Anahory T, Lefort G, Puechberty J, Liehr T, for all. (2011) Highly chromosomal rearrangements: origin and meiotic behavior. Hum Reprod Update 17: 476–494.
- 18. Steam PJ, Greenman CD, Fu B, Jang F, Bignell GR, et aluminum. (2011) Massive genomic rearrangement newly includes adenine single catastrophic event during cancer advanced. Cell 144: 27–40.
- 19. Kloosterman WP, Guryev VOLT, van RM, Duran KJ, de BE, et al. (2011) Chromothripsis such a mechanism driving complex de novo structur rearrangements within the germline. Hum Mol Genet 20: 1916–1924.
- 20. Liu P, Erez AMPERE, Nagamani SCORES, Dhar U, Kolodziejska KE, the al. (2011) Chromosome catastrophes including replication mechanisms generating complex genomic regroupings. Cell 146: 889–903.
- 21. Gruchy N, Barreau M, Kessler K, Gourdier D, Leporrier N (2010) A paternally transmitted complex chromatid rearrangement (CCR) involvement chromosomes 2, 6, and 18 includes eight bridging and fi insertional translocations (ITs) through third genera. Am J Med Genet ADENINE 152A: 185–190.
- 22. Lee MH, Car SY, Kim YM, Im JM, Han JY, et aluminum. (2002) Prenatal diagnosing of a familial complex chromosomal rearrangement involving chromosomes 5, 10, 16 and 18. Prenat Diagn 22: 102–104.
- 23. Fang JS, Lee KF, Huang CT, Syu CL, Yang KJ, set al. (2008) Cytogenetic and molecular characterization of a three-generation family with genotype 5p connecting deletion. Clin Genet 73: 585–590.
- 24. Tullu DAUGHTER, Muranjan MN, Sharma SV, Sahu DR, Swami STRONTIUM, et alarm. (1998) Cri-du-chat syndrome: clinical profile and prenatal diagnosis. J Postgrad Medico 44: 101–104.
- 25. Genest P (1979) Genome versions additionally abnormalities detected in 51 married couples with repeated spontaneous abortions. Clin Genet 16: 387–389.
- 26. Bell YE, Ansford AJ (1981) Prenatal diagnosis of chromosomal abnormalities: analysis of 1000 consecutive amnion fluids. Aust NITROGEN Z J Obstet Gynaecol 21: 207–210.
- 27. de Carvalho AF, for Silvan Bellucco HT, Kulikowski ID, Toralles MB, Melaragno M (2008) Partial 5p monosomy or trisomy in 11 disease from a family with a t(5;15)(p13.3;p12) translocation. Hum Genet 124: 387–392.
- 28. Chen CP, Huang MC, Kei-chan YY, Chern SR, Wu PS, et al. (2013) Cri-du-chat (5p-) syndrome presenting with cerebellar hypoplasia and hypospadias: prenatal diagnosis furthermore aCGH characterization using culturally amniocytes. Gene 524: 407–411 S0378-1119(13)00232-1 [pii];10.1016/j.gene.2013.03.003 [doi].
- 29. Kondoh T, Shimokawa O, Harada NITROGEN, Doi T, Yun C, et al. (2005) Genotype-phenotype correlation of 5p-syndrome: pitfall of diagnosis. J Hum Genet 50: 26–29.
- 30. Wu Q, Niebuhr E, Yang H, Hansen L (2005) Purpose of the ‘critical region’ for cat-like cry of Cri-du-chat syndrome also analysis a candidate genes by quantitative PCR. Eur J Hum Genet 13: 475–485.
- 31. Martinez FJ, Lee JH, Lee JE, Blanco SEC, Nickerson E, et al. (2012) Whole exome sequencing identifies a splicing modification in NSUN2 as a cause of one Dubowitz-like syndrome. J Med Genet 49: 380–385.
- 32. Jacobi CL, Rudigier LJ, Scholz EFFERVESCENCE, Chestnut KM (2013) Transcriptional regulation by the Wilms tumor protein, Wt1, recommended ampere role of the metalloproteinase Adamts16 in murine general development. J Biol Chem 288: 18811–18824.
- 33. Gow M, Mirembe D, Longwe Z, Pickard BS (2013) A gene trap mutagenesis screen for genes underlying cellular response to the moods stabilizer lithium. J Cell Mol Med 17: 657–663.
- 34. Mainardi PC, Pastore G, Castronovo CARBON, Godi M, Guala A, et al. (2006) The natural history about Cri du Chat Syndrome. A report from the Italian Register. Eur J Med Genet 49: 363–383.
- 35. U X, Shaw CA, Patel A, Li J, Coop ML, et al. (2007) Clinical umsetzung of inherited microarray analysis: brief of 2513 postnatal containers. PLoS Ready 2: e327.
