Trisomy 9p Research Articles

Prenatal diagnosis of a distal 3p deletion associated with fetoplacental chromosomal discrepancy and confined placental mosaicism detected by array comparative genomic hybridization

ObjectiveThis study is aimed at prenatal diagnosis of a distal 3p deletion associated with fetoplacental chromosomal discrepancy and confined placental mosaicism, and providing evidence for the limitation of array comparative genomic hybridization (aCGH) on placental tissues for molecular cytogenetic characterization of prenatally detected aneuploidy. Case ReportA 30-year-old woman underwent amniocentesis at 18 weeks of gestation because of maternal anxiety. Results of amniocentesis revealed a distal deletion of chromosome 3p. A malformed female fetus was delivered at 20 weeks of gestation with brachycephaly and facial dysmorphisms, and a cytogenetic analysis of the cord blood revealed a karyotype of 46,XX,del(3)(p26.1),inv(9)(p12q13). A whole-genome aCGH on uncultured cord blood and placental tissue was performed. The aCGH on cord blood revealed a 7.4-Mb deletion at 3p26.3-p26.1. However, the aCGH on placental tissue revealed a 32.42-Mb gene dosage increase at 3p26.1-p22.1 and a 26.28-Mb gene dosage increase at 1p36.33-p36.11 in addition to a 7.4-Mb deletion at 3p26.3-p26.1, indicating confined placental mosaicism for partial trisomy 3p (3p26.1→p22.1) and mosaicism for partial trisomy 1p (1p36.33→p36.11). The 7.4-Mb deleted region of 3p26.3-p26.1 contained the following genes: CHL1, CNTN4, CRBN, LRRN1, and ITPR1. ConclusionFetal tissue and amniocytes offer more reliable resources for aCGH characterization of prenatally detected aneuploidy compared with placental tissues. A molecular cytogenetic evaluation of prenatally detected aneuploidy using placental tissue should raise concerns of confined placental mosaicism and fetoplacental chromosomal discrepancy.

Complete and pure trisomy 18p due to a complex chromosomal rearrangement in a male adult with mild intellectual disability

Complete and pure trisomy 18p due to a complex chromosomal rearrangement in a male adult with mild intellectual disability

Familial trisomy 6p in mother and daughter

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

De novo trisomy 12p in twin girls with different levels of mosaicism

We report on a pair of twins with trisomy 12p diagnosed postnatally. The girls were referred for dysmorphism and global developmental delay and have been followed from 10 months of age. They have different levels of mosaicism for both buccal cells and lymphocytes. Although their phenotypic features were similar, there were different degrees of severity which correlate with the different levels of mosaicism.

Prenatal diagnosis of partial trisomy 16p and its association with congenital diaphragmatic hernia

What's already known about this topic? Little is known about partial trisomy 16p as relatively few cases have been reported. An abnormal yolk sac and increased nuchal translucency are associated with aneuploidy and adverse pregnancy outcomes.What does this study add? We propose that congenital diaphragmatic hernia may be part of the phenotype of partial trisomy 16p. This case adds to other recent observations of congenital diaphragmatic hernia with chromosome imbalances in 16p. This report illustrates the natural progression of an abnormality, imaged by ultrasound during the first 17 weeks of pregnancy: abnormal yolk sac, increased nuchal translucency, and diaphragmatic hernia.

De novo trisomy 20p characterized by array comparative genomic hybridization: Report of a novel case and review of the literature

We report on a boy with speech delay, mental retardation, motor clumsiness, hyperactivity, dysmorphic facial features, brachytelephalangy and short stature. Electrocardiogram, echocardiography, renal ultrasound, electroencephalogram, fundoscopic exam and auditory brainstem responses were all normal. Brain magnetic resonance imaging showed a left temporal arachnoid cyst and a small pineal gland cyst.High resolution karyotype and FISH analysis detected a de novo duplication of the short arm of chromosome 20. A molecular characterization of the chromosomal anomaly was performed by array-CGH, confirming a 17.98Mb duplication of the short arm of chromosome 20 associated with a small duplication on chromosome 3p, that was shown to be maternally inherited.This is one of the few cases of de novo trisomy 20p with extensive workup, characterization at molecular level and close follow-up from the neonatal period to age 30months. We also compared the phenotype of our patient with that previously reported in literature, therefore contributing to better define the trisomy 20p syndrome and helping pediatricians and geneticists to better counsel families about the developmental prognosis of these children.

Partial Trisomy 18q and Epileptic Spasms Induced by Eating Associated With Bilateral Opercular Dysplasia

In2007,wedescribedtheclinicalandvideo-polygraphicfeaturesofa patient with reflex periodic spasms triggered by eating [d’Orsietal.,2007].Thepatientwasa30-year-old,right-handedmanwithsevereasphyxiaatbirthandsignificantintellectualdisability.Fromthe age of 25, he began to experience generalized tonic–clonicseizures,atonicdropattacksandeating-inducedrepetitiveepilepticspasmscharacterizedbysuddenheadandupperlimbsdropping.Inparticular, during the longer spasms (at least 1sec) the ictalpolygraphy showed a diffuse slow wave complex prevalent onanterior regions with an activation in crescendo-decrescendo onthe neck and the right sternocleidomastoideus muscles. Subse-quently, chromosome analysis, fluorescence in situ hybridization(FISH), and array comparative genomic hybridization (array-CGH) were performed. The array-CGH was carried out usingthe GenomeARRAY slide (TechnoGenetics Srl-Bouty Spa, Italy),containing 5,380 BAC clones, with a genomic resolution ofabout 0.5Mb, and increasing to 0.25Mb in the subtelomericregions. These studies revealed the presence of a partialtrisomy of chromosome 18 in the 18 q12.2q22.3 region (partialtrisomy 18q; see Fig. 1). The parents had normal karyotypes andarray-CGH.The relationship between chromosomal 18 anomalies and epi-lepsy was evaluated in a previous review [Grosso et al., 2005], andpartial seizures and focal EEG abnormalities were observed inpatients with 18 qDS, trisomy 18p and translocation betweenchromosome17and18.Epilepsyonsetinpatientscarryingtrisomy18p is usually during infancy, and focal seizures remitted in themajority. EEG pattern disclosed symmetric or asymmetric parox-ysmal activity in posterior regions associated with generalizedspikes and spike and waves, while brain MRI showed agenesis ofthe splenium and thin of corpus callosum.Toourknowledge,nopreviouscaseshavebeenreportedregardingthe relationship between partial trisomy 18q and epilepsy, andour patient expands the clinical spectrum and genomic character-izationoftrisomy18.Infact,fromaclinicalpointofviewageseizureonset (25 years) and seizure semiology (epileptic spasms inducedbyeating)differentiateourcasefromothersreportedintheliterature-[Grosso et al., 2005]. In addition, genetic testing based on array-CGH and FISH have revealed additional material on chromosome18, specificallya partialduplication of the longarm of chromosome18 (trisomy of 18q12.2q22.3 region), not previously associatedwith epileptic phenotype. Deletion of genes located in the distalportion of 18q seems to be important in conferring susceptibilityfor the clinical features, including epilepsy [Strathdee et al., 1995].Deletion of the long arm of the chromosome 18 is associated withepilepsy witha frequency ranging from 10% [Wilson et al., 1979] to31%[Strathdeeetal.,1995].Notablythepatientshavebeenreportedin the literature with partial duplication of the short arm of chro-mosome 18 and epilepsy, but no previous cases have been reported

Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus

Neuroblastoma is the most common solid tumor of infancy, and mutations in several genes have been implicated as playing a role in tumor development. Here, we describe a pediatric patient with a constitutional microduplication of 2p24.3 who developed Stage 4 neuroblastoma at age 11 months. He represents the sixth patient described in the literature with partial trisomy 2p and neuroblastoma. All previous cases had duplication events spanning two genes implicated in neuroblastoma, MYCN and ALK. Our patient is unique because his duplicated region includes the MYCN gene only; the ALK gene is unaffected. These data, combined with the relatively high incidence of neuroblastoma reported in partial trisomy 2p patients, support the notion that MYCN duplication should be added to the growing list of genetic factors associated with an increased risk of neuroblastoma. The mechanism of increased risk is unclear, but the fact that our patient had dramatic amplification of MYCN in his tumor suggests that a germline duplication might predispose to further amplification. Additionally, our patient has several morphologic features common to patients with partial trisomy 2p including high forehead, hypertelorism, postaxial polydactyly, and developmental delay despite having a microduplication spanning approximately 1 Mb and including just three intact genes. This case may therefore help further delineate the genotype-phenotype correlations associated with partial trisomy 2p.

Pure de novo partial trisomy 6p in a girl with craniosynostosis

Duplications of chromosome 6p are rarely reported. We present the case of a girl with a de novo trisomy 6p12.3-p21.1 who showed clinical features characteristic of this syndrome, notably facial anomalies, psychomotor delay, and recurrent respiratory tract infections. The most striking feature, however, was craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures. A review of the literature revealed that the presence of abnormal fontanelles and sutures is relatively common among patients with proximal trisomy 6p. Exclusion of the most frequently occurring craniosynostosis mutations, as well as of further chromosomal anomalies in our case, suggest the presence of a gene regulating suture formation within this region. Based on recent findings, we hypothesize that the runt-related transcription factor 2 (RUNX2) may be a reasonable candidate gene for craniosynostosis in such patients.

Genotype-phenotype analysis of recombinant chromosome 4 syndrome: an array-CGH study and literature review

BackgroundRecombinant chromosome 4, a rare constitutional rearrangement arising from pericentric inversion, comprises a duplicated segment of 4p13~p15→4pter and a deleted segment of 4q35→4qter. To date, 10 cases of recombinant chromosome 4 have been reported.ResultWe describe the second case in which array-CGH was used to characterize recombinant chromosome 4 syndrome. The patient was a one-year old boy with consistent clinical features. Conventional cytogenetics and FISH documented a recombinant chromosome 4, derived from a paternal pericentric inversion, leading to partial trisomy 4p and partial monosomy of 4q. Array-CGH, performed to further characterize the rearranged chromosome 4 and delineate the breakpoints, documented a small (4.36 Mb) 4q35.1 terminal deletion and a large (23.81 Mb) 4p15.1 terminal duplication. Genotype-phenotype analysis of 10 previously reported cases and the present case indicated relatively consistent clinical features and breakpoints. This consistency was more evident in our case and another characterized by array-CGH, where both showed the common breakpoints of p15.1 and q35.1. A genotype-phenotype correlation study between rec(4), dup(4p), and del(4q) syndromes revealed that urogenital and cardiac defects are probably due to the deletion of 4q whereas the other clinical features are likely due to 4p duplication.ConclusionOur findings support that the clinical features of patients with rec(4) are relatively consistent and specific to the regions of duplication or deletion. Recombinant chromosome 4 syndrome thus appears to be a discrete entity that can be suspected on the basis of clinical features or specific deleted and duplicated chromosomal regions.

Case Report 3p partial trisomy and 13q partial monosomy with congenital malformations and psychomotor developmental delay

We examined a girl presenting neuropsychomotor developmental delay and multiple malformations including antenatal and postnatal growth retardation, congenital heart defect, and facial dysmorphisms. Cytogenetic analysis was performed on peripheral blood lymphocytes with the GTG-banding technique, which revealed an unbalanced translocation: 46,XX,der(13)(13pter→13q34::3p24→3pter)pat. Karyotype analysis of the father demonstrated a balanced translocation, 46,XY,t(3;13)(p24;q34), indicating the inheritance of the derivative chromosome 13. The mother karyotype was normal. We suggest that most of the structural malformations seen in this patient are due to the 3p trisomy, while the neuropsychomotor alterations are a consequence of both chromosome aberrations.

On the significance of germline cytogenetic rearrangements at MYCN locus in neuroblastoma

BackgroundMYCN oncogene amplification is the most important prognostic factor in neuroblastoma. 25% neuroblastoma tumors have somatic amplifications at this locus but little is known about its constitutional aberrations and their potential role in carcinogenesis. Here, we have performed an array-CGH and qPCR characterization of two patients with constitutional partial 2p trisomy including MYCN genomic region.ResultsOne of the patients had congenital neuroblastoma and showed presence of minute areas of gains and losses within the common fragile site FRA2C at 2p24 encompassing MYCN. The link between 2p24 germline rearrangements and neuroblastoma development was reassessed by reviewing similar cases in the literature.ConclusionsIt appears that constitutional rearrangements involving chromosome 2p24 may play role in NB development.

Multiorgan autoimmunity in a Turner syndrome patient with partial monosomy 2q and trisomy 10p

Turner syndrome is a condition caused by numeric and structural abnormalities of the X chromosome, and is characterized by a series of clinical features, the most common being short stature and gonadal dysgenesis. An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in Turner patients.We present a unique case of mosaic Turner syndrome with a complex rearrangement consisting of a partial deletion of chromosome 2q and duplication of chromosome 10p {[46],XX,der(2)t(2;10)(2pter→2q37::10p13→10pter)[127]/45,X,der(2)t(2;10)(2pter→2q37::10p13→10pter)[23]}. The patient is affected by partial empty sella, in association with a group of multiorgan autoimmunity-related manifestations including Hashimoto's thyroiditis, celiac disease, insulin-dependent diabetes mellitus (Type 1 diabetes, T1D), possible autoimmune inner ear disease with sensorineural deficit, preclinical Addison disease and alopecia universalis. The patient was previously described at the age of 2.4years and now re-evaluated at the age of 14years after she developed autoimmune conditions. AIRE gene screening revealed heterozygous c.834 C>G polymorphism (p.Ser278Arg) and IVS9+6G>A variation, thus likely excluding autoimmune polyendocrine syndrome Type 1 (APECED). Heterozygous R620W polymorphism of the protein tyrosine phosphatase non receptor type 22 (PTPN22) gene was detected in patient's DNA. SNP-array analysis revealed that autoimmunity-related genes could be affected by the partial monosomy 2q and trisomy 10p.These data suggest that early genetic analysis in TS patients with complex associations of multiorgan autoimmune manifestations would permit a precise diagnostic classification and also be an indicator for undiscovered pathogenetic mechanisms.

Two Cases of Partial Trisomy 4p and Partial Trisomy 14q

We present clinical and cytogenetic data on 2 cases of partial trisomy 4p and partial trisomy 14q. Both patients had an extra der(14)t(4;14)(p15.31;q12) chromosome due to a 3:1 segregation from a balanced translocation carrier mother. Array analyses indicated that their chromosomal breakpoints were similar, but there was no relationship between the 2 families. Both patients showed prominent growth retardation and psychomotor developmental delay. Other phenotypic manifestations were generally mild and variable; for example, patient 1 had a short palpebral fissure and low-set ears whereas patient 2 had a round face, asymmetric eyes, small ears, a short neck, finger/toe abnormalities, and behavioral problems.

Prenatal diagnosis of de novo partial trisomy 18p and partial monosomy 18q recurrent in a family with fatal aortic coarctation

Aortic coarctation is a life-threatening defect when it occurs with cardiorespiratory failure. Its genetic cause remains unknown. A woman was pregnant twice, both with male fetuses that had partial trisomy 18p, partial monosomy 18q, and aortic coarctation. The syndrome may relate to the aortic coarctation and pulmonary hypoplasia and is life-threatening. ArrayCGH analysis suggested a de novo 17.7Mb deletion of chromosome 18q21.33→qter (58,413,193bp to 76,116,029bp) and a de novo 12.4Mb duplication of chromosome 18pter→p11.21 (1543bp to 12,438,430bp) at the telomeric end of chromosome 18. To the best of our knowledge, the present chromosomal breakpoint with rearrangement has not been previously described. This chromosome aberration may be responsible for this syndrome.

Duplication 12p and Pallister–Killian syndrome: A case report and review of the literature toward defining a Pallister–Killian syndrome minimal critical region

Pallister-Killian syndrome (PKS) is a multisystem sporadic genetic condition characterized by facial anomalies, variable developmental delay and intellectual impairment, hypotonia, hearing loss, seizures, pigmentary skin differences, temporal alopecia, diaphragmatic hernia, congenital heart defects, and other systemic abnormalities. PKS is typically caused by the presence of a supernumerary isochromosome composed of the short arms of chromosome 12 resulting in tetrasomy 12p, which is often present in a tissue limited mosaic state. The PKS phenotype has also often been observed in individuals with complete or partial duplications of 12p (trisomy 12p rather than tetrasomy 12p) as the result of an interstitial duplication or unbalanced translocation. We have identified a proposita with PKS who has two small de novo interstitial duplications of 12p which, along with a review of previously reported cases, has allowed us to define a minimum critical region for PKS.

A new partial trisomy 12p with artery catheter vagus, congenital cataracts, external auditory canal, and no turbinate

We describe the prenatal diagnosis and fetal phenotype of partial trisomy 12 (p12-pter) transmitted from a maternal reciprocal translocation 6;12. Genetic analysis was conducted on umbilical cord blood for a fetus accompanied with tricuspid regurgitation and orbital hypertelorism from a 27-year-old gravida 4, para 1 after sonography at gestation 35weeks. The karyotype was unusual, with 46, XY, der (6), t (6;12) (p24; p12) mat. The pregnancy was terminated at 37 gestational weeks. The aborted fetus displayed dysmorphic features of a round flat face with prominent cheeks and high forehead, hypertelorism, short nose, broad and depressed nasal bridge, anteverted nares, deformed philtrum, open mouth, thin upper vermilion and broad everted lower lip, low-set ears and aural atresia, broad hands with simian creases, and a short neck. Fetal anatomy showed right artery catheter vagus, congenital cataract, no turbinate and external auditory canals. Through karyotype–phenotype analysis of this patient and a review of other reported cases, we believe this is a first report that expands the database of partial trisomy 12p, and is beneficial for future clinical genetic counseling. This study supports that phenotypic variability depends on the type and extent of the associated partial monosomy.

Nail and phalangeal agenesis in a patient with 4pter and 9pter duplication

We report on an 8-month-old girl with intra-uterine growth retardation, microcephaly, incomplete cleft lip, axial hypotonia, failure to thrive, and brachydactyly type B (phalangeal agenesis and absence of nails). She carried a supernumerary marker chromosome derived from chromosomes 4 and 9, leading to 4pter-q12 and 9pter-p21.2 duplication. The marker was derived from the 3:1 segregation of a maternal balanced translocation 46,XX, t(4;9)(q12;p21.2). The proposita is the first reported individual with distal phalangeal agenesis and anonychia, and trisomy 4p and partial trisomy 9p due to 3:1 segregation of a maternal reciprocal translocation.

Unbalanced Translocation Involving Partial Trisomy 9p and Partial Monosomy Yq With Neurodevelopmental Delays

We present a 4-year-old Honduran boy with mild neurodevelopmental delays, growth delays, dysmorphic features, and small genitalia. Chromosome analysis initially revealed a single X chromosome and a marker chromosome derived from the short arm of chromosome 9 which was consistent with Turner syndrome as only 1 sex chromosome could be identified. However, on further analysis, he was found to have an unbalanced translocation involving the short arm of chromosome 9 and the long arm of the Y chromosome. The translocation resulted in partial trisomy 9p and partial monosomy Yq. The patient's clinical features are felt to be the result of partial trisomy 9p. In addition, partial monosomy Yq is associated with male infertility. Testing of the patient's parents was normal, indicating this was a de novo translocation. Additional evaluations of this child and his parents allowed an accurate assessment of his diagnosis, long-term prognosis, and chance of recurrence.

Discordant phenotype in monozygotic twins with mosaic trisomy 12p in lymphocytes

We report on monochorionic diamniotic male twins discordant for the trisomy 12p syndrome. Trisomy 12p mosaicism with a supernumerary der(12)(pter > q12) was detected in approximately 50% of lymphocytes in both children. Fluorescence in situ hybridisation (FISH) revealed a high grade mosaicism of approximately 77% trisomy 12p cells in buccal smear and 85% in hair follicles in the affected twin, while in the normal developing brother an additional 12p chromosome fragment could not be detected in those tissues. Instead, in 3% of buccal smear and hair follicle cells a minute supernumerary marker chromosome comprising central portions of chromosome 12 was observed. Trisomy 12p mosaicism, confined to the lymphocytes of the unaffected twin, may be due to prenatal twin-to-twin transfusion, explaining the conspicuously discordant clinical phenotype. We discuss the possible sequence of events leading to the cytogenetic findings and compare the clinical phenotype presented in the affected twin with other cases of trisomy 12p and tetrasomy 12p (Pallister-Killian syndrome).