Prenatal diagnosis of a case with complete and uniform tetrasomy 12p by the utility of noninvasive prenatal testing.

PURPOSE: To report a rare type of Pallister-Killian syndrome (PKS) diagnosed prenatally by the utility of non-invasive prenatal testing (NIPT). METHODS: NIPT was performed in the first trimester. Conventional karyotyping and chromosomal microarray analysis (CMA) were performed on the amniotic samples in the second trimester. Copy number variation sequencing (CNV-seq) was used for the validation of fetal skin and the placental tissue after pregnancy termination. RESULTS: NIPT results showed increased signal from chromosome 12p. Subsequent prenatal diagnostic testing by karyotype revealed 47, XY, +i (12p), and CMA displayed four copies of 12p: 12p13.33-12p11.1(173786_34835641) × 4. The CNV-seq results of the fetal skin and the fetal side of placenta showed four copies of 12p13.33-p11 and an estimated chimeric duplication of 34.08 Mb (chimerism ratio: 10%) in 12 p13.33-p11, respectively. However, no abnormality was detected by CNV-seq at the maternal side of placenta. CONCLUSIONS: Our findings suggest that a positive signal from chromosome 12p on NIPT should raise suspicion for PKS. With the wide application of NIPT, the true positive of incidental finding is expected to increase.

The first case report of distal 16p12.1p11.2 trisomy and proximal 16p11.2 tetrasomy inherited from both parents.

Recurrent copy number variants in the chromosomal region 16p11.2 are among the most frequent genetic causes of neurodevelopmental disorders. The increasing prevalence of brain structural anomalies is also associated with 16p11.2 deletions and duplications. We report on a four-year-old boy with microcephaly, trigonocephaly, and dysmorphic features. The patient also exhibited motor delay and autism spectrum disorder. Microarray analysis showed a single-copy gain of a 1.187 kb segment in the 16p12.1p11.2 region and a two-copy gain of a 525 kb segment in the 16p11.2 region. Parental analysis revealed a 1.7 Mb duplication at the 16p12.1p11.2 (BP1-BP5 region) in the father and a 525 kb duplication in the 16p11.2 region (BP4-BP5) in the mother. The patient inherited the entire abnormality from each parent and, as a result, presented with partial trisomy of the 16p12.1p11.2 region and partial tetrasomy of the 16p11.2 region. The MLPA P343 Autism-1 Probemix was used to verify the copy number gains in the 16p11.2 region detected by chromosomal microarray analysis. Double duplications are very rare chromosomal rearrangements. The phenotype for distal 16p12.1p11.2 trisomy (BP1-BP3) and proximal 16p11.2 (BP4-BP5) tetrasomy is unknown. To our knowledge, this is the first patient described in the literature who inherited 16p11.2 duplications from both parents.

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.

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.

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.

Autism spectrum disorder associated with 49,XYYYY: case report and review of the literature.

BACKGROUND: Sex chromosome aneuploidies occur in approximately one in 420 live births. The most frequent abnormalities are 45,X (Turner syndrome), 47,XXX (triple X), 47,XXY (Klinefelter syndrome), and 47,XYY. The prevalence of males with more than one extra sex chromosome (e.g. 48,XXYY or 48,XXXY) is less common. However, the literature provides little information about the cognitive and behavioural phenotype and the natural history of the disease. We report the clinical, neurocognitive, social cognitive and psychiatric characterization of a patient with 49,XYYYY syndrome. CASE PRESENTATION: The patient presented with a complex phenotype including a particular cognitive profile with intellectual deficiency and autism spectrum disorder (ASD) with limited interests. Moreover, social anxiety disorder with selective mutism and separation anxiety disorder were observed (DSM-5 criteria, MINI Assessment). CONCLUSION: It is now admitted that 49,XYYYY has unique medical, neurodevelopmental and behavioural characteristics. Interestingly, ASD is more common in groups with Y chromosome aneuploidy. This clinical report suggests that understanding the cognitive and social functioning of these patients may provide new insights into possible therapeutic strategies, as cognitive remediation or social cognitive training.

Partial tetrasomy 11q resulting from an intrachromosomal triplication of a 22 Mb region of chromosome 11.

Intrachromosomal triplications are complex chromosomal rearrangements which arise during meiosis or mitosis and lead to a tetrasomic dose of the affected genomic regions. We describe a female patient harboring an intrachromosomal triplication who presented to the Genetics clinic with dysmorphic features, including telecanthus, flat facial profile, and prognathism, short stature, widely spaced nipples, multiple allergy complaints, loose bowel movements, and mild speech delay. Microarray analysis showed a copy number gain of a 22.37 Mb region of chromosome 11 between bands 11q14.1 and 11q22.1. This region contains 95 genes and seven microRNAs, none of which have been implicated in a disease resulting from increased gene dosage. FISH analysis using a probe targeted to the middle of the segment of the copy number gain yielded a pattern indicative of a tetrasomy via an intrachromosomal triplication, with three signals on the long arm of one homologue of chromosome 11 and the fourth on the other homologue. Subsequent FISH analysis showed that the middle triplicated fragment was positioned in an inverted orientation relative to the outer fragments. To investigate the mechanism by which the intrachromosomal triplication occurred, SNP microarray analysis was performed. These results were consistent with the presence of multiple haplotypes in the tetrasomic region and suggest that the intrachromosomal triplication in our patient arose in one parent during meiosis. © 2017 Wiley Periodicals, Inc.

Clinical implications of serial versus isolated biliary fluorescence in situ hybridization (FISH) polysomy in primary sclerosing cholangitis.

BACKGROUND: Cholangiocarcinoma (CCA) is a leading cause of death in patients with primary sclerosing cholangitis (PSC). Biliary polysomy detected by fluorescence in situ hybridization (FISH) helps to identify patients with early CCA, but not all PSC patients with polysomy develop CCA. Here, we examined the features and clinical outcomes of PSC patients with serial versus isolated polysomy. METHODS: All patients with PSC who underwent ≥1 endoscopic retrograde cholangiography (ERC) with FISH testing at Mayo Clinic, Rochester from 2008-2011 were identified. Patients diagnosed with CCA at the time of initial polysomy were excluded. Serial polysomy was defined as polysomy on ≥2 ERCs; isolated polysomy was defined as polysomy once followed by all nonpolysomy results. The primary outcome was the diagnosis of CCA. RESULTS: Twenty-seven patients with polysomy and ≥1 subsequent ERC with FISH were identified. Of these, 11 (40.7%) had serial polysomy and 16 (59.3%) had isolated polysomy. CCA was more likely to be diagnosed in patients with serial versus isolated polysomy (36.4% vs. 6.3%; p = .046). Overall, four patients (36.4%) with serial polysomy and three (18.8%) with isolated polysomy underwent liver transplantation (LT), with time to LT being significantly shorter for the former (14.0 vs. 65.4 months; p = .0003). CONCLUSIONS: Biliary polysomy reverted in ≥50% of patients with PSC; this group appears to be at decreased risk of CCA compared to those with serial polysomy. Nevertheless, both groups should be followed closely, and those with serial polysomy may benefit from early LT evaluation.

The genetic landscape of infantile spasms.

Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole-exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.

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.

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.

Biliary multifocal chromosomal polysomy and cholangiocarcinoma in primary sclerosing cholangitis.

OBJECTIVES: Polysomy detected by fluorescence in situ hybridization (FISH) is associated with cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC). However, a subset of PSC patients with polysomy do not manifest CCA even after long-term follow-up. It is unknown if patients with chromosomal gains detected by FISH in multiple areas of the biliary tree (i.e., multifocal polysomy, MFP) are more likely to be diagnosed with CCA than patients with unifocal polysomy (UFP). Therefore, our aim is to determine whether patients with MFP are more likely to manifest CCA compared with patients with other chromosomal abnormalities including UFP and other FISH subtypes. METHODS: We performed a retrospective review of PSC patients without a mass lesion who underwent FISH testing at our institution from 1 January 2005 to 1 July 2013. RESULTS: Three-hundred and seventy-one PSC patients were included. Compared with patients with UFP, those with MFP were more likely to have weight loss (32 vs. 9%), suspicious cytology (45 vs. 13%) and develop serial polysomy (91 vs. 35%). MFP was associated with CCA (hazard ratio (HR), 82.42; 95% confidence interval (CI), 24.50-277.31) and was the strongest predictor of cancer diagnosis. Suspicious cytology (HR, 26.31; 95% CI, 8.63-80.24) and UFP (HR, 13.27; 95% CI, 3.32-53.08) were also predictive of CCA. MFP, UFP and suspicious cytology remained associated with CCA in the multivariable model. CONCLUSIONS: Compared with other FISH subtypes, MFP is the strongest predictor of CCA. However, patients with UFP and suspicious cytology (regardless of FISH status) are also at an increased risk for CCA.

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.

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.

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.

Imprinted Genes on Chromosome 6 Are Unlikely to Cause Hydatidiform Mole. A Report of Two Cases.

BACKGROUND: Hydatidiform moles are associated with an excess of paternal genome set(s) or abnormal imprinting of multiple imprinted genes. However, it appears unlikely that all imprinted genes are relevant for the pathogenesis of a hydatidiform mole. CASES: We studied two rare cases of triploid, diandric moles that were tetrasomic for chromosome 6. DNA-marker analysis showed that in one mole the fourth chromosome 6 originated in the father, and in the other mole the fourth chromosome 6 originated in the mother. Histopathologic revision disclosed that both moles were partial moles with no significant difference in the phenotypes. CONCLUSION: It is unlikely that a major gene involved in the pathogenesis of hydatidiform mole, or a major gene involved in determining the severity of the molar phenotype, is located on chromosome 6.

Unique features of the transcriptional response to model aneuploidy in human cells.

BACKGROUND: Aneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far. RESULTS: Here we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers. CONCLUSIONS: Our analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor.

Clinical outcome: a monosomy 18p is better than a tetrasomy 18p.

We report the clinical and laboratory data of 2 patients with different rearrangements involving the short arm of chromosome 18, one with an isochromosome 18p (tetrasomy 18p) and the other with an 18p deletion (monosomy 18p by translocation t(15;18)). Based on molecular cytogenetic findings including high-resolution SNP array, FISH, and multiplex fluorescence PCR, we compared the clinical phenotypes of the 2 patients with other reported patients with 18p deletion, trisomy 18, and isochromosome 18p syndromes to obtain genotype/phenotype correlations. Our findings suggest that a partial monosomy 18p has the better clinical outcome than a tetrasomy 18p.

Supernumerary isochromosome 1, idic(1)(p12), leading to tetrasomy 1q in Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive mature B-cell neoplasm. The cytogenetic hallmark are MYC-involving translocations, most frequently as t(8;14)(q24;q32). Additional cytogenetic abnormalities are seen in the majority of cases. The most frequent additional aberration involves the long arm of chromosome 1, either as partial or complete trisomy 1q. A very rare additional aberration is a supernumerary isochromosome 1q, i(1)(q10), resulting in tetrasomy 1q. The biological significance of this aberration is unclear. We present a highly aggressive case of BL in a child with immature B-cell immunophenotype (IP) and supernumerary i(1)(q10). Diagnostic karyotyping showed 47,XY,+i(1)(q10),t(8;14)(q24;q32)[2]/47,idem,del(15)(q24)[21]/46,XY[2]. aCGH analysis detected a gain of 1p12qter and a loss of 15q22q25. FISH analysis confirmed the isodicentric chromosome 1, which has not previously been reported in BL. In the literature, supernumerary i(1)(q10) was found in 11 cases of which >80% presented with immature B-cell IP and >60% relapsed or died. Tetrasomy 1q resulting from supernumerary idic(1)(p12) or i(1)(q10) is a rare genetic event in BL and probably associated with immature B-cell IP. We propose that high amplification of genes on chromosome 1p12qter may contribute to the BL IP and disease progression.