1p36 Deletion Research Articles

Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search

BackgroundThe interstitial 6p22.3 deletions concern rare chromosomal events affecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways.Case presentationWe report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes.ConclusionsIdentification and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion.

Abnormalities Of 12p Are Associated With High-Risk Acute Myeloid Leukemia: A Children's Oncology Group Report

IntroductionAbnormalities of 12p are relatively rare in acute myeloid leukemia (AML), but are of particular interest because ETV6, an ETS family transcription factor that frequently acts as a tumor suppressor, maps to 12p13. In pediatric AML the recurrent t(7;12)(q36;p13) has been recognized in addition to other heterogeneous 12p abnormalities which results in the rearrangement or deletion of ETV6. Recently, a Medical Research Council study found that AML patients with 12p abnormalities have a poor prognosis. To date, abnormalities of 12p have been categorized as standard cytogenetic risk in Children's Oncology Group (COG) AML trials, but there are limited data on their frequency, morphologic classification, and concomitant gene mutations or chromosome abnormalities. ObjectiveTo evaluate characteristics and prognostic significance of 12p abnormalities in AML in the COG trial AAML0531. MethodsAAML0531 is a recently completed COG trial that enrolled patients between 2006 and 2010. Central review of cytogenetics was conducted on 981 of 1070 enrolled patients (non-Down syndrome) with de novo AML. Abnormalities of 12p were classified into 3 groups: 1) the t(7;12) or variants thereof; 2) abnormalities of band 12p13 other than the t(7;12) that were confirmed or highly suggestive of ETV6 rearrangement (other ETV6R); and 3) abnormalities resulting in loss of the band 12p13 (ETV6Loss). The entire group of children with 12p abnormalities (N=32) as well as the three subgroups were compared with children (N=949) without 12p abnormalities, with respect to demographics, frequency of gene mutation, additional cytogenetic abnormalities and survival. ResultsAbnormalities of 12p were identified in 32 (3.3%) of patients. 8 patients had a t(7;12) after central review (6 were missed in the local laboratory's initial submission); 10 had otherETV6R, and 14 had ETV6Loss. The median age of the 12p group was significantly lower (median, 5.8; range, 0.2–18.2) than the non-12p group (median, 9.9; range, 0.003–29.8; P=.018). Notable was the very young age of patients with the t(7;12) (median, 0.6; range, 0.2–6.4; P=.004), with 88% <2 years. In the 12p group, there were no CEBPA mutations; 1 FLT3-ITD and 2 NPM1 mutations (in the other ETV6R and ETV6Loss groups). These frequencies of genetic mutations were not significantly different from those in the non-12p group. Patients with 12p abnormalities were significantly less likely to have associated low-risk cytogenetic abnormalities of inv(16) or t(8;21) compared to the non-12p group [t(8;21) 0% vs 15%, P = .016 and inv(16) 0% vs 11% , P=.041]. Further, the proportion of patients with t(9;11) was 0% in the t(7;12) group compared to 20%, 21% and 21% in the other ETV6R, ETV6Loss, and non-12p groups, respectively. Six of 8 patients with t(7;12) had +19 as a secondary abnormality which was absent in the other 12p groups. Six of 7 patients with ETV6Loss had complex karyotypes with >6 abnormalities, compared to 0% in the other 12p groups and 4% in the non-12p groups (P<.002). On the basis of karyotype classification strategy in AAML0531 no patient with 12p abnormalities was low risk, 29 were standard risk, and 3 were high risk [due to presence of -5/5q- or -7].The 12p abnormality group had a worse 3-year OS (28±17% vs. 69±3%, P<.001) and worse 3-year EFS (14±13% vs. 51±3%, P<.001) compared with the non-12p group. For those patients who achieved CR, the RR from end of induction 1 was 37±4% for non-12p vs. 83±40% for the 12p group (P<.001). 3-year OS was 54±40% for the t(7;12), 35±32% for the otherETV6R and 11%±19% for ETV6Loss (P<.03); 3- year EFS rates were 15±28%, 13±3%, and 14±19%, respectively (P>.1). ConclusionsPatients with abnormalities of 12p should be considered for categorization as high-risk with respect to cytogenetic stratification for AML. Given the subtle nature of the t(7;12) and other ETV6 rearrangements and their prognostic implications FISH for ETV6 is recommended upfront for the evaluation of any young patient with AML with a +19 as a secondary abnormality and in any patient suggestive of 12p deletion or rearrangement. Disclosures:No relevant conflicts of interest to declare.

Inherited unbalanced reciprocal translocation with 3q duplication and 5p deletion in a foetus revealed by cell-free foetal DNA (cffDNA) testing: a case report

BackgroundSince 2011, screening maternal blood for cell-free foetal DNA (cffDNA) fragments has offered a robust clinical tool to classify pregnancy as low or high-risk for Down, Edwards, and Patau syndromes. With recent advances in molecular biology and improvements in data analysis algorithms, the screening’s scope of analysis continues to expand. Indeed, screening now encompassess additional conditions, including aneuploidies for sex chromosomes, microdeletions and microduplications, rare autosomal trisomies, and, more recently, segmental deletions and duplications called copy number variations (CNVs). Yet, the ability to detect CNVs creates a new challenge for cffDNA analysis in couples in which one member carries a structural rearrangement such as a translocation or inversion.Case presentationWe report a segmental duplication of the long arm of chromosome 3 and a segmental deletion of the short arm of chromosome 5 detected by cffDNA analysis in a 25-year-old pregnant woman. The blood sample was sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay. G-band karyotyping in amniotic fluid only detected an abnormality in chromosome 5. Next-generation sequencing in amniocytes confirmed both abnormalities and identified breakpoints in 3q26.32q29 and 5p13.3p15. The foetus died at 21 weeks of gestation due to multiple abnormalities, and later G-band karyotyping in the parents revealed that the father was a carrier of a balanced reciprocal translocation [46,XY,t(3;5)(q26.2;p13)]. Maternal karyotype appeared normal.ConclusionThis case provides evidence that extended cffDNA can detect, in addition to aneuploidies for whole chromosomes, large segmental aneuploidies. In some cases, this may indicate the presence of chromosomal rearrangements in a parent. Such abnormalities are outside the scope of standard cffDNA analysis targeting chromosomes 13, 18, 21, X, and Y, potentially leading to undiagnosed congenital conditions.

Wolf-Hirschhorn Syndrome with Hyperparathyroidism: A Case Report and a Narrative Review of the Literature.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.

Genomic Alterations Important for the Prognosis in Patients with Follicular Lymphoma Treated on SWOG Study S0016

Background: Follicular lymphoma (FL) is a common, indolent, yet typically incurable disease characterized by clinical and genetic heterogeneity. Recent studies suggested that TNFRSF14 mutation and 1p36 deletion were associated with worse outcome in FL and that TNFAIP3 mutation on 6q occurred at FL transformation. However, no genomic biomarkers are currently in clinical use for prognostic and therapeutic decisions. We aimed to identify novel genomic aberrations associated with prognosis of patients with FL in the context of a randomized cooperative group trial (Press 2013 JCO).Patients and Methods: We employed a comprehensive genomic array testing strategy to assess the common genomic abnormalities, including copy number aberrations (CNAs), copy-neutral loss-of-heterozygosity (cnLOH), and common cancer gene mutations. Our study set includes all patients enrolled in the SWOG FL study S0016 with available pre-treatment tissue specimens. Chromosome genomic array testing (CGAT) has been performed on 255 archived formalin-fixed, paraffin embedded (FFPE) lymphoma tissue specimens. A SWOG pathologist reviewed all tissues prior to CGAT to ensure that each sample met the diagnostic criteria for FL and had at least 30% tumor content. The OncoScan platform was used for CGAT with data analysis performed by Nexus Express. Statistical analysis was performed using the Cox-proportional hazard regression model. Hazard ratio (HR) and 95% confidence interval (CI) were estimated from the multivariate model. Statistical significance was determined at an alpha-level of 0.05 after Bonferroni adjustment for multiple comparisons.Results: CGAT was successful on 247 samples (97%), and 245 entered into final data analysis. Most samples (>90%) showed multiple chromosome abnormalities (median 8, range 1-64). The most frequently affected chromosome arms were: 1p (54%), 6p (39%), 6q (38%), 18q (36%), 12q or 16p (33%), and 1q (32%). Specific common CNAs were deletions of 1p, 6q, 10q, and 17p, gains of X, 1q, 2, 7, 8q, 12, 17q, and 18, and cnLOH of 1p, 6p, and 16p. Univariate analysis for progression free survival (PFS) identified several aberrations significantly associated with prognosis at unadjusted .05 level. Multivariate analysis adjusting for FLIPI risk, bulky disease, and combined serum b2M and LDH levels demonstrated that three markers, 9p deletion or cnLOH, 12p gain, and 17q gain, remained significant for PFS (HR 2.0, 1.7, and 1.7 for 9p, 12p, and 17q, respectively). Comparing treatment arms, the hazard of progression or death is 0.6 times less comparing CHOP+I-131 vs. CHOP+R if a patient has no abnormality in Xp (P=0.02). When we further analyzed specific segmental aberrations, eight regions were independent prognostic markers for overall survival (OS) in multivariate analysis and seven regions for PFS (see Figure 1 for representative markers). Specifically, patients with abnormal CDKN2A/B (p16) were 3.2 times more likely to progress early (P<.0001) while those with abnormal TP53 (17p) and TNFRSF12A/CREBBP (16p) loci were 3.9 and 6.7 times, respectively, more likely to die early (P=0.0001). For treatment effect on OS, six patients with abnormal TNFRSF12A/CREBBP (16p) showed an HR 0.06 when receiving CHOP+I-131 compared to CHOP+R (P=0.02). In particular, comparing patients who progressed vs. not at two years, Fisher's exact test identified seven differential genomic regions. Among these, FANCL region on 2p and USP3 region on 15q were also significant (P<.005) in Cox regression analysis limiting 2-year follow-up with the goal to focus on early events.Conclusion: We confirmed the frequent 1p (TNFRSF14) and 6q (TNFAIP3) deletions in FL reported in literature. More importantly, we identified several genomic aberrations that showed independent prognostic value for FL patients. Among these, deletions and cnLOH of CDKN2A (9p), CREBBP (16p) and TP53 (17p) are of significant interest. These genomic aberrations may add to currently utilized clinical risk stratification as a means to identify high risk patients at diagnosis of FL. Certain markers that showed treatment arm effect may serve as predictive markers.Support: This work was supported by Affymetrix Inc., NIH/NCI National Clinical Trials Network (NCTN) grants CA180888 and CA180819, and in part by GlaxoSmithKline. [Display omitted] DisclosuresPress:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Hsi:Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Cellerant Therapeutics: Research Funding; Abbvie: Research Funding; Eli Lilly and Co.: Research Funding. Leonard:Celgene: Consultancy, Research Funding; Roche: Consultancy. Friedberg:Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.

Prenatal diagnosis of a fetus with chromosome 18p deletion and duplication

To assess the value of chromosomal microarray analysis (CMA) to verify a fetus with partial 18p deletion signaled by non-invasive prenatal testing. G-banding chromosomal karyotyping analysis was carried out on amniotic fluid sample of the fetus and peripheral blood samples from the parents. Amniotic DNA was also subjected to CMA analysis. The fetus was also subjected to systematic ultrasound scan. The fetus was found to have a karyotype of 46,XX,18p+. CMA has revealed a 5 Mb deletion at 18p11.32-p11.31, a 2.9 Mb duplication at 18p11.31-p11.23, and a 2.5 Mb duplication at 18p11.23-p11.22. No chromosomal aberration or microdeletion/microduplication was detected in either parent. Non-invasive prenatal testing and CMA are both sensitive for the detection of chromosomal microdeletions and microduplications. CMA can help with clarification of genotype-phenotype correlation and facilitate prenatal diagnosis and genetic counseling for the family.

Chromosome 10 abnormality predicts prognosis of neuroblastoma patients with bone marrow metastasis

BackgroundNeuroblastoma (NB) is the most common extracranial solid tumor in children. It is known for high heterogeneity and concealed onset. In recent years, the mechanism of its occurrence and development has been gradually revealed. The purpose of this study is to summarize the clinical characteristics of children with NB and abnormal chromosome 10, and to investigate the relationship between the number and structure of chromosome 10 abnormalities and NB prognosis.MethodsChromosome G-banding was used at the time of diagnosis to evaluate the genetics of chromosomes in patients with NB and track their clinical characteristics and prognosis. All participants were diagnosed with NB in the Medical Oncology Department of the Beijing Children’s Hospital from May 2015 to December 2018 and were followed up with for at least 1 year.ResultsOf all 150 patients with bone marrow metastases, 42 were clearly diagnosed with chromosomal abnormalities. Thirteen patients showed abnormalities in chromosome 10, and chromosome 10 was the most commonly missing chromosome. These 13 patients had higher LDH and lower OS and EFS than children with chromosomal abnormalities who did not have an abnormality in chromosome 10. Eight patients had both MYCN amplification and 1p36 deletion. Two patients had optic nerve damage and no vision, and one patient had left supraorbital metastases 5 months after treatment.ConclusionsThe results indicated that chromosome 10 might be a new prognostic marker for NB. MYCN amplification and 1p36 deletion may be related to chromosome 10 abnormalities in NB. Additionally, NB patients with abnormal chromosome 10 were prone to orbital metastases.

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.

Clinical report of a neonate carrying a large deletion in the 10p15.3p13 region and review of the literature

BackgroundTerminal deletion of chromosome 10p is a rare chromosomal abnormality. We report a neonatal case with a large deletion of 10p15.3p13 diagnosed early because of severe clinical manifestations.Case presentationOur patient presented with specific facial features, hypoparathyroidism, sen sorineural deafness, renal abnormalities, and developmental retardation, and carried a 12.6 Mb deletion in the 10p15.3 p13 region. The terminal 10p deletion involved in our patient is the second largest reported terminal deletion reported to date, and includes the ZMYND11 and GATA3 genes and a partial critical region of the DiGeorge syndrome 2 gene (DGS2).ConclusionOn the basis of a literature review, this terminal 10p deletion in the present case is responsible for a specific contiguous gene syndrome. This rare case may help the understanding of the genotype–phenotype spectrum of terminal deletion of chromosome 10p.

Genomic analysis of primary malignant melanoma of the esophagus.

e21515 Background: Primary malignant melanoma of the esophagus (PMME) is an exceedingly rare disease but behave more aggressively and have a poorer prognosis. No specific histopathological classification and therapy strategies have been established for this type of disease due to lack of both tumor biological and genetics perception to PMME. Methods: We performed whole exome sequencing on 29 dissections including 23 primary tumors and 6 metastatic lymph nodes from 18 PMME patients. The genetic characteristics including somatic mutations and copy number variation (CNV) of PMME were compared to 398 skin cutaneous melanoma (SKCM), 67 mucosal melanoma (MM) and 79 uveal melanoma (UVM). Using multi-region sequencing, we reconstructed the phylogenetic structure and inferred the evolutionary mode. Results: We found that PMME/MM have similar genomic patterns to SKCM but distinct from UVM. Frequently mutated driver genes such as MUC16, BRAF, NRAS, NF1, KMT2C, POLE, PTPRT, RANBP2 appeared in both SKCM and PMME/MM cohorts. Of note, pathway enrichment analysis using identified driver genes revealed that melanoma pathway and MAPK signaling pathway were among the top affected pathways in MM/PMME as well as in SKCM. UVR-associated single base substitution signature 7 (SBS7) was not a dominant signature (median: 0.17, range:0̃0.79) in PMME/MM but 99 percent (89/90) of them do have it. An overall concordant trend in genome instability was found between PMME and SKCM. Significant CNV events at arm level showed the similar changes in PMME and SKCM, including amplification regions of 1q, 6p, 7p, 8q, 15q, 20p and deletion of 10p, 10q, 11p. CDKN2A loss appeared as a shared focal event by PMME and SKCM. To elucidate the evolution trajectory of spatially separated samples, we also performed multi-region sequencing, and the phylogenetic analysis suggested that whole genome doubling (WGD) was an early and clonal event, which preceded the majority of somatic mutations and CNV. Most driver genes such as NF1, RANBP2 and MUC16 mutated after WGD except TP53. Above findings suggested that WGD might be capable of promoting ongoing genome instability and shaping the evolution in PMME. Moreover, parallel evolution of RANBP2 was recurrently observed indicating the existence of constraints and selection. Conclusions: Our data showed that PMME/MM exhibited genetic features very similar to SKCM so it might not be excluded from treatments currently used for common SKCM.

Case report: The spectrum of autoimmune thyroid disease in association with chromosome 18p deletion syndrome

Case report: The spectrum of autoimmune thyroid disease in association with chromosome 18p deletion syndrome

Application analysis of noninvasive prenatal testing for fetal chromosome copy number variations in Chinese laboratories

Objective: To investigate the general situation, detection range, testing reagents, and clinical performance of non-invasive prenatal testing (NIPT) for fetal chromosomal copy number variations (CNVs) in Chinese laboratories. Methods: The National Center for Clinical Laboratories of the National Health Commission designed a questionnaire for the detection of CNVs by NIPT, which included the investigation of whether the laboratory has carried out NIPT to detect CNVs and its testing scope, reagents/platforms, intended uses, screening populations and clinical performance. The questionnaires were distributed to 355 laboratories in 31 provinces, autonomous regions, and municipalities across the country on October, 2020. Further, the feedbacks were statistical analyzed. Results: Two hundred and twenty-eight laboratories had performed NIPT to detect CNVs, including 116 types of CNVs, and more than 95% of laboratories chose to detect the CNVs of 5p15 deletion, 22q11.2 deletion, 1p36 deletion, and 15q11.2 deletion. All testing reagents used were laboratory-developed tests and were based on massive parallel sequencing, the minimum amount of sequencing data was 3-15 M reads, the detection limit of fetal fraction was 3%-5%, and the minimum size of variants that can be detected was 1-5 Mb. The proportion of laboratories that apply CNVs testing for daily project, voluntary requirements of patients, and scientific research were 58.8% (134/228), 57.5% (131/228), and 20.6% (47/228), respectively. One hundred and thirty-four laboratories were fully or partially aware of the clinical performance of NIPT to detect microdeletion/microduplication syndromes, and the laboratories' declared sensitivity of NIPT for Cri du Chat syndrome, 22q11.2 deletion syndrome, 1p36 deletion syndrome, and Angelman syndrome were 50.0%-100%, 60.0%-100%, 50.0%-100%, and 33.3%-100%, and the positive predictive values were 9.0%-50.0%, 18.0%-100%, 20.0%-30.0%, and 20.0%. Conclusion: The detection of CNVs by NIPT in Chinese laboratories need to be standardized. Laboratories should detect CNVs with clear clinical significance in accordance with the guidelines, conduct performance validation of the reagents, then perform NIPT test and provide adequate interpretation after mastering the clinical performance sufficiently.

Genetic aspects of Ebstein anomaly and related heart diseases

Ebstein anomaly is a congenital heart disease, which is characterized by the presence of atrialized portion of the right ventricle, formed as a result of displacement of the tricuspid valve leaflets into the right ventricle and their partial adherence to the underlying myocardium. Atrialized portion in the right ventricle occupies the space between the fibrous annulus of the right atrioventricular orifice and the functional annulus of tricuspid valve, which represents a zone of closure of free (non-adherent to the underlying myocardium) edges of its leaflets. Ebstein anomaly is very rarely isolated, and can be combined with a number of heart diseases and be an integral part of hereditary syndromes. Currently, the role of genetic research in the investigation of the etiology of human diseases as well as understanding of the relationship between different diseases is increasing. The review presents literature data on the combination of Ebstein anomaly with other heart diseases (congenital heart diseases, Wolf-Parkinson-White syndrome, cardiomyopathies, including left ventricular noncompaction), inter alia, within the scope of hereditary syndromes (Noonan syndrome, 8p deletion syndrome, 18q deletion syndrome, 1p36 deletion syndrome, Pierre Robin syndrome). Genetic factors (gene and chromosomal mutations) lying at the core of Ebstein anomaly, as well as heart diseases combined with it, are highlighted. The analysis of published data suggests that Ebstein anomaly is a monogenic disease, and is characterized by allelic and locus genetic heterogeneity. The combination of Ebstein anomaly with other heart diseases is based on their genetic linkage.

RERE deficiency contributes to the development of orofacial clefts in humans and mice.

Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7 and GRHL3. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest (CNC) cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH and that RERE expression in CNC cells and their derivatives is required for normal palatal development.

Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis

Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3− CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.

IUGR is Commonly Observed among Prenatally Diagnosed Chromosome 4p Deletion Syndrome

Objective: our study aimed at retrospectively assessing the abnormal prenatal ultrasound findings of chromosome 4p deletion syndrome. Methods: 21 cases with abnormal sonographic signs revealed 4p deletion by Chromosome Microarray (CMA) in this retrospective analysis. Clinical information and molecular basis of this cohort were compared with those from other two groups in China, the critical region related to special ultrasound findings was mapped with the smallest regions of overlap. Results: This is the largest prenatal series to evaluate the prenatal ultrasound features of 4p deletion syndrome detected by CMA. Firstly we refined the relationship between the genomic coordinates with IUGR in chromosome 4p terminal deletion syndrome. Additional chromosomal abnormalities was identified in 12 cases. Intrauterine embryonic arrest was diagnosed at first trimester for 9 cases. The most consistent ultrasound indicator was IUGR (95.5%), and the smallest region response for IUGR correspond to a 2.05Mb at 4p16.3-pter (chr4: 68,345-2,121,057, hg19). Increased Nuchal Translucency (NT) could be a risk factor for predicting WHS at first-trimester pregnancy with the rate of 16.6% from our data. A 3.6Mb microdeletion located at 4p16.3-pter (chr4: 68,345-3,753,422, hg19) might be the candidate region associated with increased NT. Conclusion: We identified IUGR as the most common feature in prenatal 4p terminal deletion and Wolf-Hirschhorn syndrome. The existence of additional CNVs may contribution to possible explanations for the clinical heterogeneity of this syndrome. Prenatal findings of IUGR, increased NT or early spontaneous abortion should warrant the diagnosis of 4p terminal deletion WHS.

50 Years Ago in TheJournalofPediatrics: Understanding the Molecular Basis of 11p13 Deletion

50 Years Ago in TheJournalofPediatrics: Understanding the Molecular Basis of 11p13 Deletion

Detection of deletions in 1q25, 1p36 and 1pTEL and chromosome 17 aneuploidy in oral epithelial dysplasia and oral squamous cell carcinoma by fluorescence in situ hybridization (FISH)

ObjectiveTo identify chromosome deletions in 1q25, 1p36 and 1pTEL, and chromosome 17 ploidy status in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Material and methodsSamples from 57 OED and 63 OSCC were selected. FISH was performed using centromeric probes 17 and n LSIR 1p36/LSI 1q25 Dual Color Probe. ResultsIn OED, deletions were found only in 1pTEL region (29.8%). In OSCC, there was a higher frequency of deletion in 1pTEL (79.4%), followed by 1p36 (73.0%), and 1q25 (20.6%). Advanced TNM clinical stages (III/IV) showed all the deletions studied; at early clinical stages (I/II) of OSCC, deletions were observed only in 1pTEL. The frequency of deletion in 1p36 was 17.0 times higher in OSCC at advanced clinical stages (PR: 17.00). The median number of cell nuclei with chromosome 17 aneuploidy was higher in OSCC than in OED (P < 0.001). Early clinical stages of OSCC showed lower median number nuclei with aneuploidy when compared to advanced tumors (P < 0.05). Tumors harboring deletions in 1p36, 1q25 and 1pTEL revealed higher median numbers of trisomic/polysomic nuclei when compared to lesions exhibiting no abnormalities in chromosome 1 (P < 0.05). ConclusionA higher prevalence of chromosomal abnormalities was found in OSCC than in OED, while in OSCC, higher abnormalities were present in lesions with higher TNM staging. 1pTEL deletion and monosomy of chromosome 17 are possible markers for progression of OED to OSCC. 1p36 deletion and trisomy/polysomy of chromosome 17 could be markers of worse prognosis of OSCC.

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

265 Hemivertebra: systematic review of cases with cytogenetic abnormalities, associated anomalies and proposed prenatal management

To identify cases of hemivertebra with abnormal cytogenetic studies and assess for other associated anomalies in order to provide more accurate patient counseling and prenatal management. This systematic review was conducted using PubMed (including Cochrane database) and Ovid Medline from inception through November 2019. Studies were deemed eligible for inclusion if hemivertebra with abnormal cytogenetic studies was identified in the fetal, neonatal, or infant period. Studies that described other vertebral anomalies were excluded. We identified 17 cases of hemivertebra with cytogenetic abnormalities among a total of 324 cases (5%) in our review. These include partial tetrasomy 4q, mosaic trisomy 4, mosaic trisomy 7, mosaic trisomy 9, mosaic trisomy 18q, mosaic trisomy 18; trisomy 7, trisomy 15q with monosomy 6q, partial trisomy 22; duplication of 2p; 4p- deletion, 17p deletion, 18p deletion, 18q22.2 deletion, 22q13.3 deletion; ring chromosome 21, and Fanconi’s anemia. 29% (5/17) were diagnosed prenatally, 47% (8/17) at birth, and 18% (3/17) postnatally. All cases had prenatally or postnatally diagnosed associated anomalies. 29% (5/17) had associated anomalies identified prenatally, including ear anomalies, CNS abnormalities, micrognathia, congenital heart defects, renal anomalies, clubfeet, and fetal growth restriction. Postnatally diagnosed anomalies commonly included: CNS (41%, 7/17), cardiac (53%, 9/17), skeletal (71%, 12/17) and genitourinary (59%,10/17). Hemivertebra with abnormal cytogenetic testing was always associated with malformations from other organ systems that could be missed by prenatal ultrasound alone. Those include CNS, cardiovascular, musculoskeletal, and genitourinary anomalies. Fetal echocardiogram is recommended due to the considerable association with congenital heart defects. Fetal neurosonography or MRI should be considered. Of those receiving genetic testing, karyotype or SNP microarray should be considered due to the common presence of mosaicism.