Trisomy 9p Research Articles

Prenatal diagnosis of the Dandy–Walker malformation associated with partial trisomy 12p and distal 15q deletion

Dandy-Walker malformation (DWM) is characterized by complete or partial agenesis of the cerebellar vermis, cyatic dilatation of the forth ventricle, and enlarged posterior fossa. However, the mechanism is still not completely understood up to now. In this study, we reported a rare case that a foetus with DWM showed partial trisomy 12p and distal 15q deletion. Karyotype analysis and chromosomal microarray analysis (CMA) were not always concordant with each other, and it is suggested that they should be performed for prenatal genetic diagnosis together. DWM is a rare central nervous system malformation, reported in 1/25-30,000 live births, characterized by complete or partial agenesis of the cerebellar vermis, cyatic dilatation of the forth ventricle, and enlarged posterior fossa (Kumar et al. 2001; Klein et al. 2003; Agrawal et al. 2016). The neurological development of children with DWM may range from normal to severely retarded, and cause variable clinical feature. Although several efforts have been made to explore its pathogenesis, however, it is still not completely understood. During the past decade, some genetic loci, microdeletion or duplication have been reported to be associated with DWM, such as 9p trisomy, partial deletions of the long arm of chromosome 13, genes ZIC1 and ZIC4 (von Kaisenberg et al. 2000; McCormack et al. 2003; Grinberg et al. 2004). In the present study, we describe a prenatal diagnosis case that a foetus with DWM on ultrasound scanning accepted genetic testing, and it revealed a microduplication of 12p13.33p11.1 and microdeletion of 15q11.2 in 750K single nucleotide polymorphism (SNP) array, while it showed 46,XX,der(8)(8pter→8q24::12p10→12qter),i(12)(p10) in karyotyping.

Fetal Cystic Hygroma Associated with Terminal 2p25.1 Duplication and Terminal 3p25.3 Deletion: Cytogenetic, Fluorescent in Situ Hybridization and Microarray Familial Characterization of Two Different Chromosomal Structural Rearrangements.

We report a prenatally diagnosed case of partial trisomy 2p and partial monosomy 3p, resulting from unbalanced translocation (2;3)(p25.1;p25.3) of paternal origin. Parents were non consanguineous Caucasians, with familial history of recurrent miscarriages on the father’s side. Detailed sonographic examination of the fetus showed a septated cystic hygroma measuring 6 mm at 13 weeks’ gestation. Karyotyping and fluorescent in situ hybridization (FISH) analysis of cultured amniotic fluid cells revealed an unbalanced translocation der(3)t(2;3)(p25.1; p25.3) and apparently balanced inv(3)(p13p25.3) in a fetus. Parental cytogenetic evaluation using karyotyping and FISH analysis showed the presence of both a balanced translocation and a paracentric inversion in father t(2;3) (p25.1;p25.3) inv(3)(p13p25.3). Microarray analysis showed a 11.6 Mb deletion at 3p26.3-p25.3 and duplication of 10.5 Mb at the 2p25.3-p25 region. The duplicated region at 2p25.1p25.3 contains 45 different genes, where 12 are reported as OMIM morbid genes with different phenotypical implications. The deleted region at 3p26.3-p25.3 contains 65 genes, out of which 27 are OMIM genes.Three of these (CNTN4, SETD5 and VHL) were curated by Clingene Dosage Gene Map and were given a high haplo-insufficiency score. Genes affected by the unbalanced translocation could have contributed to some specific phenotypic changes of the fetus in late pregnancy. The application of different cytogenetic methods was essential in our case, allowing the detection of different types of structural chromosomal aberrations and more thorough genetic counseling for future pregnancies.

750 Constitutional reciprocal translocation t(9;22) and pregnancy

To determine the spectrum of cytogenetic abnormalities and outcomes in unbalanced offspring of asymptomatic carriers of a constitutional balanced t(9;22) translocation. A systematic literature review was performed using PubMed and Scopus from inception through March 18, 2020 identifying articles discussing constitutional translocation of chromosomes 9 and 22. We also added a previously unpublished case from our institution of a maternal constitutional balanced t(9;22) translocation. There were 16 patients with balanced t(9;22) translocation, which includes our case. Of these patients, 13 were maternal and 3 were paternal balanced translocations. There were 15 probands with unbalanced translocations from these 16 parental carriers, 1 maternal carrier did not have an unbalanced offspring. Of the probands, 13 were live births, one a missed abortion, and one an elective termination. The spectrum of derivative unbalanced cytogenetics of the livebirth probands were: trisomy 9p syndrome (6 cases), co-existing trisomy 9p syndrome and DiGeorge syndrome (3 cases), co-existing 9q subtelomere deletion syndrome & DiGeorge syndrome (1 case), 9q subtelomere deletion syndrome (1 case), and DiGeorge syndrome (1 case). The phenotypic outcome of unbalanced probands included cardiac defects (5 cases), neurological findings (7 cases), intellectual disabilities (6 cases), urogenital anomalies (3 cases), and respiratory or immune dysfunction (3 cases). If a parent/potential parent is a known constitutional balanced t(9;22) translocation carrier, they should be counseled about the increased risk of having a child with an unbalanced translocation with the aforementioned spectrum of cytogenetic and congenital abnormalities. Additionally, if a pregnancy has been diagnosed with an unbalanced translocation from a carrier parent, families should be counseled on the predicted clinical presentation for the given unbalanced derivative.

Prenatal detection of terminal 9p24.3 microduplication encompassing DOCK8 gene: A variant of likely benign.

Trisomy 9p is one of the most common chromosomal partial trisomies in newborns. However, reports on prenatal 9p microduplications are rare in the clinic. This study aimed to examine the genotype–phenotype correlation and assess the clinical significance of 9p24.3 microduplication encompassing the DOCK8 gene. Eight pregnant women underwent amniocentesis for cytogenetic and genetic testing for various indications for prenatal diagnosis from January 2019 to January 2020. Chromosomal karyotypic analysis was performed on G-band metaphases that were prepared from cultured amniotic fluid cells. Chromosomal microarray analysis was carried out to detect chromosomal copy number variations. We also performed a literature review on clinical data on similar 9p24.3 microduplications to determine the genotype–phenotype correlation. We detected 123–248-kb microduplications in the region of 9p24.3 (chr9: 208454–469022), involving part of or the entire DOCK8 gene. The indications for prenatal diagnosis mainly focused on the risk of maternal serum screening for trisomy 21/18, advanced maternal age, and increased nuchal translucency. No evident structural abnormalities were observed for all fetuses, except for case 5 who presented with increased nuchal translucency in prenatal ultrasound findings. Follow-up of postnatal health was performed and showed no apparent abnormalities for cases 1 to 6 after birth. The parents of case 7 chose to terminate the pregnancy while the parents of case 8 chose to continue the pregnancy. We propose that 9p24.3 microduplications that encompass part of or the entire DOCK8 gene are variants that might be benign. However, further large-scale studies are necessary to evaluate the clinical pathogenicity. For prenatal cases with 9p24.3 microduplication, postnatal health and growth should be followed up and assessed regularly from childhood to adulthood.

Molecular characterization of a complex small supernumerary marker chromosome derived from chromosome 18p: an addition to the literature

BackgroundSmall supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype–phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients.Case presentationHere we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype.ConclusionsOur case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling.

Clozapine treatment in schizophrenia, intellectual difficulty and trisomy 5p

There is a considerable paucity of empirical data on the use of clozapine in people with intellectual disability, and to the authors’ knowledge these are the first published data on its use in a patient with trisomy 5p and with a diagnosis of schizophrenia. In this case we describe a patient with learning difficulties and a diagnosis of trisomy 5p and schizophrenia that has responded remarkably to clozapine treatment despite numerous additional clinical risk factors.

A case of partial trisomy 2p with cleft palate treated by palatoplasty

A case of partial trisomy 2p with cleft palate treated by palatoplasty

Nonmosaic Trisomy 19p13.3p13.2 Resulting from a Rare Unbalanced t(Y;19)(q12;p13.2) Translocation in a Patient with Pachygyria and Polymicrogyria

Nonmosaic trisomy involving 19p13.3p13.2 is a very uncommon abnormality. At present, only 12 cases with this genetic condition have been reported in the literature. However, the size of the trisomic fragment is heterogeneous and thus, the clinical spectrum is variable. Herein, we report the clinical and cytogenetic characterization of a 5-year-old boy with nonmosaic trisomy 19p13.3p13.2 (7.38 Mb), generated by a derivative Y chromosome resulting from a de novo unbalanced translocation t(Y;19)(q12;p13.2). We demonstrated the integrity of the euchromatic regions in the abnormal Y chromosome to confirm the pure trisomy 19p. Our patient shares some clinical features described in other reported patients with pure trisomy 19p, such as craniofacial anomalies, developmental delay, and heart defects. Different to previous reports, our case exhibits frontal pachygyria and polymicrogyria. These additional features contribute to further delineate the clinical spectrum of trisomy 19p13.3p13.2.

Prenatal diagnosis of maternal partial trisomy 9p23p24.3 and 14q11.2q21.3 in a fetus: a case report

ObjectiveThis study aimed to report a fetus with maternal partial trisomy 9p and 14q and the phenotype detected in ultrasound.MethodsThe chromosome rearrangements in the fetus were characterized by G-banding and chromosome microarray analysis based on single nucleotide polymorphism (SNP) array of cultured amniocytes and compared with the parents’ karyotypes.ResultsThe fetal abnormal karyotype was 47,XY,+der(14)(9;14)(p23;q22). The SNP array revealed a duplicate 11.8-Mb 9p23-p24.3 fragment and a duplicate 29.6-Mb 14q11.2-q21.3 fragment. The peripheral blood karyotype of the mother was 46,XX,t(9;14)(p23;q22), while the father’s was normal at the level of 300~400 bands. A high-resolution karyotype analysis conformed the same abnormality of the mother at the level of 550~650 bands. These results indicated that the fetal chromosomal abnormality probably derived from the mother. The fetal nuchal translucency thickness was 3.5 mm, and the fetal heart was detected with around 1.0-mm ventricular defect by the ultrasound examination at 12-week gestation. The couple decided to terminate the pregnancy. They opted for in vitro fertilization and embryo transfer for the fourth pregnancy, which was successful.ConclusionsThe SNP array combined with cytogenetic analysis was particularly effective in identifying abnormal chromosomal rearrangements. These methods combined with the existing database information and fetal ultrasonography might provide a comprehensive and efficient way for the prenatal assessment of fetal situations. Preimplantation genetic diagnosis might effectively assist those women with an adverse pregnancy history in their next pregnancy.

Trisomy 12p Syndrome Presenting with Fetal Growth Restriction and Polyhydramnios

A 39-year-old nulliparous woman was referred at 36+6 weeks gestational age, and a prenatal fetal ultrasonography examination found fetal growth restriction (2,190 g <5%), polyhydramnios (amniotic fluid index: 31.76 cm), and absent end-diastolic flow in the umbilical artery. A male baby was born, and fetal dysmorphism including round face, long philtrum, low-set ears, chest retraction, edematous hands and feet, and a simian line on both hands were identified. He was diagnosed with trisomy 12p [der(18)t(12;18)(p11.2;p11.31)] by chromosomal study. The father’s chromosomes appeared normal; however, the mother’s chromosomes had a balanced translocation identified as t(12;18)(p11.2;p11.31). Patent ductus arteriosus, germinal matrix hemorrhage, and hemivertebrae were diagnosed, and respiratory distress, hyperinsulinemic hypoglycemia, and hypothyroidism were also detected. The combination of fetal growth restriction and polyhydramnios may be a significant sign of chromosomal abnormalities, and targeted sonography and a chromosomal analysis should be offered prenatally in such cases.

A Case of Dental Treatment in a Patient with Partial Trisomy 7p Syndrome

A Case of Dental Treatment in a Patient with Partial Trisomy 7p Syndrome

Trisomy 9p. A brief clinical, diagnostic and therapeutic description.

Trisomy 9p is characterized by the partial or complete duplication of the short arm of chromosome 9. It is one of the most common autosomal structural abnormalities in newborn infants. This is a relatively poor gene region, so it may be more compatible with survival. It is characterized by delayed mental and psychomotor growth, craniofacial dysmorphisms, skeletal alterations, central nervous system abnormalities, congenital heart disease, and, to a lesser extent, kidney disorders. To establish a diagnosis, it is necessary to perform a cytogenetic study with G bands and, if available, fluorescence in situ hybridization complemented with comparative genomic hybridization for a better understanding of the genotype-phenotype correlation. Assessment should be interdisciplinary and encompassing a timely family genetic counseling, together with available therapeutic options in an early manner.

Chromosomal Heterogeneity of the G-401 Rhabdoid Tumor Cell Line: Unusual Partial 7p Trisomy.

Rhabdoid tumor is a very aggressive and hardly curable pediatric malignancy. It commonly starts in the kidneys but also can occur in the brain, liver, and other organs. The treatment of this tumor usually involves a combination of surgery, radiation, and chemotherapy. Because this tumor is rare, there is still limited experience with a defined standard of care. Cytogenetic analysis is an important routine method to monitor chromosomal aberrations. We have analyzed metaphases of the G-401 rhabdoid tumor cell line. In these cells we have observed metaphases with derivative chromosome 12 arising from partial trisomy 7p. With increasing passage number the numbers of metaphases having this derivative chromosome 12 were found to be higher. In passage number 2 only one metaphase had this pathological chromosome 12. By passage number 10 and passage number 15 about 25 and 95% of this derivative chromosome 12 were found, respectively. We were able to subclone G-401 cells by limiting dilutions and successfully separated cells having apparently normal karyotypes from cells having derivative chromosome 12. Using the cell proliferation assay we showed that clones possessing the derivative chromosome 12 grew more rapidly than clones with normal chromosomes. The cell cycle analysis confirmed this observation. Overall, in this study we describe for the first time a 7p triplication in a rare rhabdoid tumor of kidney. Both types of clones described in this study could be used as a preclinical model to study the involvement of partial chromosome 7 alterations in the development of rhabdoid tumors.

A Systematic Clinical Review of Prenatally Diagnosed Tetrasomy 9p.

Tetrasomy 9p was first described in 1973 and approximately 68 cases with a variable phenotype have been reported to date with 22 of them being detected prenatally. The objective of this study was to review prenatally-reported cases of tetrasomy 9p thus far and to identify ultrasound phenotypes that may be suggestive of this specific syndrome. A PubMed database search was done in February 2018 without any restriction of publication date orjournals, with the use of the following keywords: tetrasomy 9p, tetrasomy 9p prenatal, mosaic tetrasomy 9p, mosaic tetrasomy 9p prenatal, isochromosome 9p, duplication 9p prenatal, trisomy 9p prenatal. Reported cases were included if the clinical presentation and diagnostic approach of each case was clearly described. The most common characteristics of prenatally-detected tetrasomy 9p are intrauterine growth retardation (IUGR, 57.0%), central nervous system (CNS) abnormalities (59.0%), skeletal anomalies (29.0%), genitourinary and renal anomalies (29.0%) and cardiac defects (29.0%). The phenotypic spectrum of tetrasomy 9p is rather unspecific as these findings are commonly associated with other chromosome anomalies, as well as microdeletion/microduplication or monogenic syndromes. The combination of early fetal morphology and diagnostic genetic testing enables a definite tetrasomy 9p diagnosis and effective further pregnancy management.

OR38 Unusual HLA a locus resolution for a patient with partial trisomy 6p syndrome

OR38 Unusual HLA a locus resolution for a patient with partial trisomy 6p syndrome

Trisomy 12p Syndrome Secondary to a Balanced Maternal Translocation [46,XX, t(12;22)(p11.2;p13)

Trisomy 12p is a rare chromosomal anomaly. It causes dysmorphic features, multiple congenital anomalies, neonatal complications, and mental retardation. We present a case of complete and pure trisomy 12p syndrome resulting from malsegregation of a balanced translocation of maternal origin, with a comprehensive literature review.

Treatment of Labial Ulcer Induced by Twisted and Delayed Eruption of Upper Right First Incisor in Patient with 9p Trisomy Syndrome：A Case Report

Treatment of Labial Ulcer Induced by Twisted and Delayed Eruption of Upper Right First Incisor in Patient with 9p Trisomy Syndrome：A Case Report

Identification of De Novo and Rare Inherited Copy Number Variants in Children with Syndromic Congenital Heart Defects.

Congenital heart defects (CHDs) are the most common birth defects in neonatal life. CHDs could be presented as isolated defects or associated with developmental delay (DD) and/or other congenital malformations. A small proportion of cardiac defects are caused by chromosomal abnormalities or single gene defects; however, ina large proportion of cases no genetic diagnosis could be achieved by clinical examination and conventional genetic analysis. The development of genome wide array-Comparative Genomic Hybridization technique (array-CGH) allowed for the detection of cryptic chromosomal imbalances and pathogenic copy number variants (CNVs) not detected by conventional techniques. We investigated 94 patients having CHDs associated with other malformations and/or DD. Clinical examination and Echocardiography was done to all patients to evaluate the type of CHD. To investigate for genome defects we applied high-density array-CGH 2 × 400K (41 patients) and CGH/SNP microarray 2 × 400K (Agilent) for 53 patients. Confirmation of results was done using Fluorescent in situ hybridization (FISH) or qPCR techniques in certain cases. Chromosomal abnormalities such as trisomy 18, 13, 21, microdeletions: del22q11.2, del7q11.23, del18 (p11.32; p11.21), tetrasomy 18p, trisomy 9p, del11q24-q25, add 15p, add(18)(q21.3), and der 9, 15 (q34.2; q11.2) were detected in 21/94 patients (22%) using both conventional cytogenetics methods and array-CGH technique. Cryptic chromosomal anomalies and pathogenic variants were detected in 15/73 (20.5%) cases. CNVs were observed in a large proportion of the studied samples (27/56) (48%). Clustering of variants was observed in chromosome 1p36, 1p21.1, 2q37, 3q29, 5p15, 7p22.3, 8p23, 11p15.5, 14q11.2, 15q11.2, 16p13.3, 16p11.2, 18p11, 21q22, and 22q11.2. CGH/SNP array could detect loss of heterozygosity (LOH) in different chromosomal loci in 10/25 patients. Array-CGH technique allowed for detection of cryptic chromosomal imbalances that could not be detected by conventional cytogenetics methods. CHDs associated with DD/congenital malformations presented with a relatively high rate of cryptic chromosomal abnormalities. Clustering of CNVs in certain genome loci needs further analysis to identify candidate genes that may provide clues for understanding the molecular pathway of cardiac development.

Genotype/Phenotype correlation with partial duplications of 6p and 6q

Partial trisomy 6p and 6q are rare and clinical features include craniofacial changes, mental retardation and developmental delay. The study aims to correlate the genotype/ phenotype of a 6p and 6q duplication carrier. MVSN, female, single daughter of nonconsanguineous and healthy young couple. From an earlier relationship, the father had a 13-year-old son. Delivered by C-section, gestation of 37 weeks. The clinical analysis revealed: microcephaly, brachycephaly, syndromic facies, prominent forehead, hyperarousalism, strabismus, short nose, anteverted nares, smooth philtrum, thin lip, upper lip tented, micrognathism, dental anomalies, low-set ears, slender fingers, nails malformation, digitiform thumb, bilateral flat foot, hypotonia and neuropsychomotor developmental delay (NPMD). In the physical examination performed at 2 years of age, weight was 7,570 Kg (&lt;3,58%), length was 74 cm (&lt;3,95%) and cephalic perimeter was 43 cm (&lt;2%). Classic cytogenetic techniques were performed (GTG banding and high resolution GTG), molecular cytogenetic (FISH) and cytogenetic (aCGH). The karyotype showed a mosaicism 47, XX, + mar [9]/46, XX [11] (ISCN, 2016). The parental karyotype was normal. The chromosomal changes found by aCGH indicate a genetic gain at chromosomal regions 6p11.2?q12 and 6q14.1?q14.3 with a size of 10.335 Mb and 10. 765 Mb, respectively. The patient presented mosaicism of a marker chromosome (sSMC) identified by the technique of FISH as coming from chromosome 6. In region 6p11.2?q12 the genes present are: PRIM2, GUSBP4, MTRNR2L9, KHDRBS2, LGSN, PTP4A1, PHF3, EYS and MCART3P. Heart defects and kidney problems were cited in the literature as being characteristic of trisomy 6p. However, patient did not present any of these phenotypic changes. The region 6q14.1?q14.3 contains more than 20 genes. The clinical signs found in patient such as: developmental delay, mental retardation, forehead prominent, short nose and thin lips has been described in other studies in the literature as characteristic of 6q trisomy. The presence of mosaicism excludes the possibility of sSMC as the sole responsible for the patient's phenotype. Our study correlates the phenotypic characteristics presented by the patient with partial trisomy 6q collaborating for family genetic counseling.

Age-Related Chromosomal Aberrations in Patients with Diffuse Large B-Cell Lymphoma: An In Silico Approach.

BackgroundIn diffuse large B-cell lymphoma (DLBCL), chromosomal aberrations are known to increase with advancing age. Our study aims to determine if there are other genetic aberrations associated with DLBCL based on age.MethodsUsing the Mitelman Database of Genetic Aberrations, we were able to find 749 cases of DLBCL with genomic aberrations with a median age of 62 years. Patients with DLBCL chromosomal aberration analysis results were divided into four groups based on age (0 - 30, 31 - 50, 51 - 70, > 71 years) and examined by chi-square analysis and Mantel-Cox for survival analysis.ResultsTen aberrations were found to be significant with a particular age range: t(2;3), trisomy 19p13, trisomy 18q21, trisomy 3, trisomy 7, trisomy 14, trisomy 16, trisomy 18, monosomy 3 and monosomy 11, and survival ranged from 7 to 25 months.ConclusionThis suggests that patients with DLBCL are likely to accumulate specific translocations depending on their age at the onset of DLBCL.