Partial tetrasomy 18 mosaicism: Pre and postnatal diagnosis of a unique pattern.

OBJECTIVE: To present prenatal diagnosis and cytogenetic characterization of a unique pattern of partial tetrasomy 18 mosaicism. CASE REPORT: A 34-year-old woman underwent amniocentesis at 25 weeks of gestation due to anomalies detected in obstetric ultrasound. It revealed a de novo supernumerary partial isochromosome 18 in 11 of 37 metaphases of cultured amniocytes. The karyotype was 47,XX,+idic(18) (q12.3)[11]/46,XX[26]. Elective cesarean section was performed at 33 weeks of gestational age due to anhydramnios. A female symmetric small for gestational age baby with dysmorphic features and an Apgar score of 9/10/10 was born. She had a good clinical outcome during hospitalization. Postnatal peripheral blood karyotype was normal. Interphase fluorescence in situ hybridization in a sample of the oral mucosa confirmed the prenatal diagnosis. At three months of corrected age she had a normal psychomotor development. CONCLUSION: To the best of our knowledge, this is the first reported case of mosaic partial tetrasomy 18 including segments of the long arm. This newborn's relatively mild phenotype highlights the challenges of prenatal genetic counselling in mosaic cases with fetal anomalies.

Histone chaperone-mediated co-expression assembly of tetrasomes and nucleosomes.

The nucleosome, a basic unit of chromatin found in all eukaryotes, is thought to be assembled through the orchestrated activity of several histone chaperones and chromatin assembly factors in a stepwise manner, proceeding from tetrasome assembly, to H2A/H2B deposition, and finally to formation of the mature nucleosome. In this study, we demonstrate chaperone-mediated assembly of both tetrasomes and nucleosomes on the well-defined Widom 601 positioning sequence using a co-expression/reconstitution wheat germ cell-free system. The purified tetrasomes and nucleosomes were positioned around the center of a given sequence. The heights and diameters were measured by atomic force microscopy. Together with the reported unmodified native histones produced by the wheat germ cell-free platform, our method is expected to be useful for downstream applications in the field of chromatin research.

The first post-natal clinical description of true mosaic complete tetrasomy 21: A case report.

Tetrasomy 21 is a rare occurrence. Only 14 cases have been reported in the literature, 8 of which are partial tetrasomy cases and 6 which are complete tetrasomy cases. Of the incidences, no proband with true complete tetrasomy 21 has survived the neonatal period. We report complete mosaic tetrasomy 21 in a female infant with the typical Down syndrome phenotype, including Hirschsprung's disease and atrioventricular (AV) canal defect. This is in contrast to cases of partial tetrasomy 21, which often have an atypical trisomy 21 presentation and multiple nonspecific traits, including short stature, microcephaly, and developmental delays. This case demonstrates the difference in clinical presentation between the partial and complete subtype of tetrasomy 21 and provides the first postnatal clinical picture of an infant with true mosaic complete tetrasomy 21.

Tetrasomy of 11q13.4-q14.3 due to an intrachromosomal triplication associated with paternal uniparental isodisomy for 11q14.3-qter, intrauterine growth restriction, developmental delay, corpus callosum dysgenesis, microcephaly, congenital heart defects and facial dysmorphism.

OBJECTIVE: We present tetrasomy of 11q13.4-q14.3 due to an intrachromosomal triplication associated with paternal isodisomy of uniparental disomy (iso-UPD) for 11q14.3-qter and multiple abnormalities. CASE REPORT: A 30-year-old primigravid woman was found to have intrauterine growth restriction (IUGR) in the fetus since 28 weeks of gestation, and a 2056-g baby was delivered at 38 weeks of gestation with fetal distress. The baby postnatally manifested hypotonia, microcephaly, facial dysmorphism of micrognathia, retrognathia and low-set ears, ventricular septal defect, atrial septal defect, tricuspid regurgitation and corpus callosum dysgenesis. A single nucleotide polymorphism (SNP) array comparative genomic hybridization analysis on the DNA extracted from the peripheral blood revealed the result of arr 11q13.4q14.3 (71,567,724-89,547,851) × 4, arr 11q14.3q25 (89,466,484-134,942,626) hmz [GRCh37 (hg19)] with a 17.980-Mb triplication of 11q13.4-q14.3 encompassing the genes of GRM5 and MAP6, and loss of heterozygosity for a 45.476-Mb region of 11q14.3-qter consistent with iso-UPD for 11q14.3-qter. Polymorphic DNA marker analysis confirmed paternal iso-UPD for 11q14.3-qter. Cytogenetic analysis of the blood revealed a karyotype of 46,XY,trp(11) (q13.4q14.3). The parental karyotypes were normal. When follow-ups at age 2 years, the neonate manifested physical and psychomotor developmental delay and intellectual disability. CONCLUSION: Tetrasomy 11q13.4-q14.3 may present the phenotype of IUGR, developmental delay, corpus callosum dysgenesis, microcephaly, congenital heart defects and facial dysmorphism.

Prenatal diagnosis of a de novo tetrasomy 15q24.3-25.3: Case report and literature review.

BACKGROUND: Terminal duplication on chromosome 15q is a rare chromosomal variation. Affected individuals show similar features such as growth dysplasia or the development of frontal bossing, body deformities, facial abnormalities, and genitourinary or cardiovascular disorders. However, it is not yet clear whether such 15q repeats lead to identifiable patterns of clinical abnormalities. Therefore, the purpose of this study was to analyze the prenatal diagnostic results and clinical manifestations of a fetus with 15q duplication and to summarize the literature. METHODS: The case was a fetus at 28 weeks of gestation. The risk of Down syndrome from second-trimester screening was 1/140. Prenatal ultrasound and amniocentesis were performed, and chromosomal microarray analysis (CMA) was used for genetic analysis. RESULTS: The fetus had abnormal clinical features, including intracardiac echogenic focus in the left ventricle, an aberrant right subclavian artery, and growth delay. The fetal chromosomal karyotype was 46,XX,15q?,12q?,21pstk+, and CMA revealed a 10.163 Mb duplication at 15q24.3-q25.3. The couple chose to terminate the pregnancy after careful consideration. CONCLUSIONS: The combination and rational application of cytogenetics technology and molecular genetics technology such as CMA will open up the field of clinical application and provide useful genetic counseling for parents of fetuses carrying such chromosomal duplications.

Diagnosis and clinical delineation of mosaic tetrasomy 5p.

OBJECTIVE: Our objective was to review the phenotypic and genetic characteristics of tetrasomy 5p from the fetal period until adulthood including prenatal diagnostic evaluations. BACKGROUND: Tetrasomy 5p is a rare chromosomal abnormality. Of the 14 reports, most document mosaic tetrasomy 5p resulting from a supernumerary marker chromosome or isochromosome. There is a wide range of phenotypic manifestations with severity related to more proximal breakpoints and the degree of mosaicism. DESIGN: We conducted a systematic review using Scopus, PubMed Central® and Ovid MEDLINE® from inception through July 1, 2018 for all articles describing tetrasomy 5p. All articles describing the syndrome of tetrasomy 5p were included. RESULTS: Of the 15 included cases, 13 exhibited mosaic tetrasomy and two had complete tetrasomy identified by amniocentesis. The most common features include seizures (8/11 live births, 73%), hypotonia (7/11 live births, 64%), developmental delay (7/9 cases that reached childhood, 78%), abnormal external ears (6/11 live births, 55%), short stature (6/11 live births, 55%), ventriculomegaly (5/11 live births, 45.5%) and congenital heart defect (6/15 cases, 40%). The clinical phenotype ranged in severity from mild with no defining characteristics to severe with seizures, developmental delay, and multiple congenital anomalies, resulting in early death. Of these 15 cases, only 6 were diagnosed prenatally by prenatal genetic testing (40%) with prenatal ultrasound identifying abnormalities in 4/6 (67%). Confined placental mosaicism (CPM) was diagnosed in six additional cases due to discordance between CVS and amniocentesis results. Four of the five live births returned for evaluation and each showed normal development. CONCLUSIONS: Fourteen out of 15 (93%) cases of tetrasomy 5p were associated with an abnormal phenotype. Once a diagnosis is made prenatally, a detailed anatomy ultrasound and fetal echocardiogram must be performed to further characterize any structural abnormalities of the fetus and potentially estimate the clinical severity. Caution should be exercised when prenatal diagnosis of mosaic tetrasomy 5p is found by chorionic villus sampling. CVS alone is insufficient to diagnose tetrasomy 5p and needs to be confirmed with amniocentesis. Our review seeks to inform clinicians on the current literature regarding tetrasomy 5p so that they may better counsel patients when this syndrome is diagnosed.

Small Supernumerary Ring Chromosome Derived from an Inverted Duplication of 13q11.2q14 in a Fetus with Coarctation of the Aorta.

Here, we report a molecular characterization of a small supernumerary marker chromosome (sSMC) derived from the most proximal region of 13q present in a fetus with coarctation of the aorta at ultrasound examination during prenatal diagnosis. Cultured umbilical cord blood cells showed a de novo extra ring-shaped sSMC in 76% of the cells using a standard banding technique. SNP array revealed a tetrasomy of about 28.4 Mb in the long arm of chromosome 13 from band 13q11 to 13q14.11 in the fetus's cells. Metaphase/interphase FISH using specific probes located at 13q11, 13q12.11, and 13q14.11, respectively, demonstrated that the supernumerary ring chromosome was derived from an inverted duplication of the region 13q11q14.11 with a conventional centromere. To the best of our knowledge, this is the first time that an inverted duplication of the most proximal region 13q11q14.11 in a ring chromosome is characterized. The findings we presented here deepen our understanding of the clinical consequences of tetrasomy in this region and may be of help for further studies of critical regions in chromosome 13.

A review of structural brain abnormalities in Pallister-Killian syndrome.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. METHODS: We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. RESULTS: We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. CONCLUSION: Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.

Obstrucción intestinal como manifestación del síndrome de Pallister-Killian / Intestinal obstruction as a manifestation of Pallister-Killian syndrome

El síndrome de Pallister-Killian (SPK) es una alteración genética rara, no hereditaria y esporádica, que se produce por un mosaicismo para la tetrasomía del brazo corto del cromosoma 12. Se manifiesta con un fenotipo típico, que se caracteriza por un aspecto facial tosco, el labio de Pallister, una nariz corta con narinas antevertidas, un puente nasal plano, hipertelorismo, orejas de implantación baja y malformadas, alopecia en la región bitemporal, anomalías en las extremidades, pigmentación irregular con manchas acrómicas e hipercrómicas y uñas hipoplásicas. Se asocia frecuentemente a hernia diafragmática, alteraciones cardiovasculares y malformaciones anorrectales. Presentamos el primer caso descrito en la literatura de SPK que se manifiesta con un cuadro de obstrucción intestinal (AU)

Pallister-Killian syndrome (PKS) is a rare, non-hereditary, sporadic mosaicism genetic disorder, caused by tetrasomy of the short arm of chromosome 12. It is expressed with a typical phenotype characterized by coarse face with broad, Pallister lip, short nose with anteverted nostrils, flat nasal bridge, hypertelorism, low and malformed ears implantation, bitemporal alopecia, limb abnormalities, irregular pigmentation with achromic and hyperchromic spots and hypoplasic nails. Frequently associated with diaphragmatic hernia, cardiovascular and anorectal malformations. We report the first case in the literature of PKS with associated symptoms of functional intestinal obstruction (AU)

Methylation and expression analyses of Pallister-Killian syndrome reveal partial dosage compensation of tetrasomy 12p and hypomethylation of gene-poor regions on 12p.

To ascertain the epigenomic features, i.e., the methylation, non-coding RNA, and gene expression patterns, associated with gain of i(12p) in Pallister-Killian syndrome (PKS), we investigated single cell clones, harboring either disomy 12 or tetrasomy 12p, from a patient with PKS. The i(12p)-positive cells displayed a characteristic expression and methylation signature. Of all the genes on 12p, 13% were overexpressed, including the ATN1, COPS7A, and NECAP1 genes in 12p13.31, a region previously implicated in PKS. However, the median expression fold change (1.3) on 12p was lower than expected by tetrasomy 12p. Thus, partial dosage compensation occurs in cells with i(12p). The majority (89%) of the significantly deregulated genes were not situated on 12p, indicating that global perturbation of gene expression is a key pathogenetic event in PKS. Three genes-ATP6V1G1 in 9q32, GMPS in 3q25.31, and TBX5 in 12q24.21-exhibited concomitant hypermethylation and decreased expression. The i(12p)-positive cells displayed global hypomethylation of gene-poor regions on 12p, a footprint previously associated with constitutional and acquired gains of whole chromosomes as well as with X-chromosome inactivation in females. We hypothesize that this non-genic hypomethylation is associated with chromatin processing that facilitates cellular adaptation to excess genetic material.

The presence of extra chromosomes leads to genomic instability.

Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.

The first de novo non-mosaic 14q11.2q13.1 tetrasomy of paternal origin.

Tetrasomy 14q11q13 is a very rare chromosome aberration. So far, only five patients with such an imbalance were described. All these patients had a de novo marker chromosome idic(14)(q13) leading to a partial tetrasomy of chromosome 14. We report on the first case of a de novo non-mosaic partial tetrasomy 14q resulted not from a marker chromosome, but from an inverted triplication on paternal chromosome 14, characterized by using FISH and SNP array. Our patient showed some anomalies described in tetrasomy 14q11q13 with striking presence of paternal UPD(14) features (blepharophimosis, small thorax, and joint contractures, developmental delay). This unique patient supports the hypothesis that 14q11q13 may contain imprinted gene(s) that contribute to the paternal UPD(14) features of joint contractures and/or blepharophimosis. This patient demonstrates the utility of parent of origin testing in patients with de novo chromosome 14 aberrations. Overdosage of 14q11.1q13.1 may cause some features related to UPD(14) phenotype.

De novo 11q13.4q14.3 tetrasomy with uniparental isodisomy for 11q14.3qter.

Interstitial triplications in conjunction with uniparental disomy (UPD) have been rarely reported. Here we report on a patient with de novo triplication at 11q13.4-q14.3 and UPD for 11q14.3-qter. Chromosomal analysis showed a karyotype of 46, XYqh+, der (11), and normal parental karyotypes. A single nucleotide polymorphism (SNP) array detected an 18.7 Mb copy number gain consistent with tetrasomy for 11q13.4-q14.3 (chr11:71,002,347 bp-89,725,167 bp, hg19) and absence of heterozygosity for a 45 Mb stretch on 11q and consistent with uniparental isodisomy at 11q14.3-qter (chr11:89,843,477 bp-134,930,689 bp, hg19) in our patient. FISH analysis using two probes on both sides of the tetrasomic region showed an inverted 11q13.4-q14.3 region between two direct oriented 11q13.4-q14.3 segments (11q13.4-q14.3::11q14.3-q13.4::11q13.4-qter). Previously reported features of duplication overlapping 11q13-q14 showed clinical variability. Our patient presented with some of those frequently described features, such as development delay, facial dysmorphism, and microcephaly but without congenital heart disease. Moreover, our patient had in addition a brain anomaly (absence of cerebellar vermis and partial absence of corpus callosum) which has not been reported. To our knowledge, this is the sixth patient reported an intrachromosomal triplication together with UPD. Interstitial 11q duplication overlapping 11q13-q14 is associated with intellectual disability/development delay, microcephaly, and facial dysmorphism but also other malformations.

Pallister-Killian syndrome: a study of 22 British patients.

BACKGROUND: Pallister-Killian syndrome is a rare, sporadic condition caused by mosaic tetrasomy of the short arm of chromosome 12 (12p). The main features are intellectual disability, seizures, dysmorphic features and a variety of congenital malformations. Most available information comes from individual case reports. We report the results of a British study into Pallister-Killian syndrome, which is the first to provide comprehensive data on a population-based sample. METHOD: A detailed phenotypical study was carried out in Great Britain. All individuals with Pallister-Killian syndrome were eligible to participate. Each participant underwent a structured history, developmental assessment and clinical examination. Buccal mucosal samples were analysed by interphase fluorescence in situ hybridization (FISH) and blood samples by array comparative genomic hybridization (CGH). Genotype-phenotype correlations were sought in these tissues and existing skin biopsy reports. RESULTS: Twenty-two patients with Pallister-Killian syndrome, ranging from 4 months to 31 years were recruited and comprehensive data on each obtained. The birth incidence was 5.1 per million live births. Array CGH only suggested the diagnosis in 15.8% but buccal FISH could have made the diagnosis in 75.0%. There was no genotype-phenotype correlation in any of the tissues studied. This study shows that the high birth weights and profound intellectual disability classically described in Pallister-Killian syndrome are not universal. Mild or moderate intellectual disability was present in 27.6% of this cohort and all birth weights were within 2.67SD of the mean. New features which have not previously been recognised as part of Pallister-Killian syndrome include anhydrosis/hypohydrosis and episodic hyperventilation, suggesting involvement of the autonomic system.

Mosaic tetrasomy 20p associated with osteoporosis and recurrent fractures.

Tetrasomy 20p is a very rare chromosome abnormality, with only two single cases previously reported in the literature, both fetuses with multiple congenital anomalies, osteopenia, and fractures. We report on the first case of mosaic tetrasomy 20p in a 13-year-old male. Amniocentesis karyotype showed mosaicism (73% of cells) for a supernumerary marker chromosome, an isodicentric chromosome 20p. At birth, cord blood karyotype was normal in all cells but uroepithelial cells showed the marker chromosome in 30% of cells analyzed. Chromosomal single nucleotide polymorphism (SNP) microarray using buccal cells confirmed the previous result with mosaicism estimated at 59% of cells. His course has been complicated by profound osteoporosis with recurrent nontraumatic fractures and vertebral compression leading to significant disability. This report describes the phenotype and evaluation of mosaic pure tetrasomy 20p syndrome and compares to nonmosaic tetrasomy 20p and trisomy 20p syndromes, both of which have been previously reported in association with osteopenia and fractures. The pathophysiology of osteoporosis in tetrasomy 20p is unknown. We hypothesize that overexpression of bone morphogenetic protein 2 may be the underlying mechanism of osteoporosis and recurrent fractures.

Mosaic tetrasomy 13q and phylloid hypomelanosis: a case report and review of the literature.

A 6-year-old girl presented for evaluation of skin discoloration. Examination revealed oval and oblong hypopigmented macules on her trunk and extremities. Cytogenetic studies and immunohistochemistry of biopsies from normally pigmented and hypopigmented skin revealed mosaicism for partial tetrasomy for 13q with low melanocyte levels in lesional skin. The patient was diagnosed with phylloid hypomelanosis (PH), a distinct clinical entity linked to abnormalities in chromosome 13. This article reviews the literature regarding PH and supports the notion that mosaicism of the melanocyte region of chromosome 13q is responsible for PH.