Subtelomeric Deletion Research Articles

Analysis of genome copy number variations in fetuses with isolated ventricular septal defect and a literature review

To assess the value of copy number variation sequencing (CNV-seq) for revealing the genetic etiology of fetuses with isolated ventricular septal defect (VSD). From December 2017 to December 2020, 69 fetuses with isolated VSD were identified at the First Affiliated Hospital of Zhengzhou University. Meanwhile, 839 similar prenatal cases were selected from public databases including Wanfang data, Wanfang Medicine, and China National Knowledge Infrastructure (CNKI) by using keywords such as "Ventricular septal defect", "Copy number variation", and "Prenatal". A total of 908 fetuses with isolated VSD were analyzed. CNV-seq was carried out for 69 fetuses. Among the 908 fetuses, 33 (3.63%) were found to harbor pathogenic CNVs, which included 11 chromosomal aneuploidies (1.21%) and 22 pathogenic CNVs (2.42%). The pathogenic CNVs have involved 12 genetic syndromes, with those known to involve the heart development including 5 cases of 22q11.21 deletion syndrome, 2 cases of 4q terminal deletion syndrome, and 1 case of 9q subtelomere deletion syndrome. The outcome of pregnancies for 15 fetuses with pathogenic CNVs was known, of which 12 were terminated, and 3 had spontaneous closure of the ventricular septum after birth, but 1 of them had other abnormalities. Fetuses with isolated VSD have a relatively high risk for chromosomal abnormalities, for which CNV-seq should be recommended.

Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia

In Africa, most rapid diagnostic tests (RDTs) for falciparum malaria recognize histidine-rich protein 2 antigen. Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes escape detection by these RDTs, but it is not known whether these deletions confer sufficient selective advantage to drive rapid population expansion. By studying blood samples from a cohort of 12,572 participants enroled in a prospective, cross-sectional survey along Ethiopia’s borders with Eritrea, Sudan and South Sudan using RDTs, PCR, an ultrasensitive bead-based immunoassay for antigen detection and next-generation sequencing, we estimate that histidine-rich protein 2-based RDTs would miss 9.7% (95% confidence interval 8.5–11.1) of P. falciparum malaria cases owing to pfhrp2 deletion. We applied a molecular inversion probe-targeted deep sequencing approach to identify distinct subtelomeric deletion patterns and well-established pfhrp3 deletions and to uncover recent expansion of a singular pfhrp2 deletion in all regions sampled. We propose a model in which pfhrp3 deletions have arisen independently multiple times, followed by strong positive selection for pfhrp2 deletion owing to RDT-based test-and-treatment. Existing diagnostic strategies need to be urgently reconsidered in Ethiopia, and improved surveillance for pfhrp2 deletion is needed throughout the Horn of Africa.

Genetic and cytogenetic screening of autistic spectrum disorder: Genotype-phenotype profiles

Autism, a pervasive developmental disorder typically characterized by repetitive behaviour, social skills deficit (or a deficit in social communication), speech and language impairments. Our prime focus is to analyze the clinical features and phenotypical behavioural changes using the diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSM IV-TR), and locating the biomarkers associated with specific autistic characters using karyotyping and fluorescence in situ hybridization (FISH) techniques. The prevalence rate of the neurexin 1 (NRXN1) gene polymorphism was also assessed in the current study. The study group involved 196 samples with 98 autistics, and equal age-matched (±2) controls based on their birth order and carrier. The participants include 35.2% males (n = 69) and 14.8% females (n = 29). The autistic and control participants were categorized based on their ages as group I (<12 yrs) with n = 62; males n = 41 (20.9%); females n = 21 (10.7%) and group II (≥12 yrs)-n = 36; males n = 28 (14.2%); females n = 08 (4.08%). Karyotyping was done for autism participants (n = 98) and the results showed that 90% of autistic participants were either the only child or the first child with a low perception and frequency in both the groups. Subsequently, we carried out the FISH assay on participants (n = 37) with higher DSM-IV TR score (≥30). Only 30 FISH tests were negative for subtelomeric deletions with NRXN1 polymorphism genotypic frequency as 62.50%, 25% and 25% for A/A, A/G and G/G genotype respectively. Our study suggests the link between a haplotype with clinical signs of autism for the single nucleotide sequence (SNP rs9636391) and links autistic characters and gene among autistic children according to their birth order, age and gender in India.

Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris.

Candida auris is an emerging fungal pathogen of rising concern due to global spread, the ability to cause healthcare-associated outbreaks, and antifungal resistance. Genomic analyses revealed that early contemporaneously detected cases of C. auris were geographically stratified into four major clades. While Clades I, III, and IV are responsible for ongoing outbreaks of invasive and multidrug-resistant infections, Clade II, also termed the East Asian clade, consists primarily of cases of ear infection, is often susceptible to all antifungal drugs, and has not been associated with outbreaks. Here, we generate chromosome-level assemblies of twelve isolates representing the phylogenetic breadth of these four clades and the only isolate described to date from Clade V. This Clade V genome is highly syntenic with those of Clades I, III, and IV, although the sequence is highly divergent from the other clades. Clade II genomes appear highly rearranged, with translocations occurring near GC-poor regions, and large subtelomeric deletions in most chromosomes, resulting in a substantially different karyotype. Rearrangements and deletion lengths vary across Clade II isolates, including two from a single patient, supporting ongoing genome instability. Deleted subtelomeric regions are enriched in Hyr/Iff-like cell-surface proteins, novel candidate cell wall proteins, and an ALS-like adhesin. Cell wall proteins from these families and other drug-related genes show clade-specific signatures of selection in Clades I, III, and IV. Subtelomeric dynamics and the conservation of cell surface proteins in the clades responsible for global outbreaks causing invasive infections suggest an explanation for the different phenotypes observed between clades.

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.

Intellectual disability and dysmorphisms in a child with 14q32.31-q32.33 deletion: a case report

INTRODUCTION: Intellectual disability and global developmental delay are frequent causes of genetic consultation requested by pediatricians. Around 30% of severe intellectual disability and 70% of mild intellectual disability do not present a defined diagnosis. OBJECTIVES: Chromosome microarray comparative genomic hybridization test is now the standard diagnosis for patients presenting unexplained global developmental delay or intellectual disability, autism spectrum disorders, and multiple congenital anomalies due to the tests sensibility, increasing the chance for a diagnosis and elucidating size and region affected. CASE REPORT: This paper reports a girl with intellectual disability, prominent hypotonia, postnatal growth retardation and several dysmorphisms with a small subtelomeric 14q terminal deletion whose diagnosis was sought during six years and only became possible through the chromosome microarray test.

Natural histories of patients with Wolf-Hirschhorn syndrome derived from variable chromosomal abnormalities.

Wolf-Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype-phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause "typical WHS facial appearance". In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted-duplication-deletion. Among 10 patients, one patient did not show "typical WHS facial appearance" although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited "typical WHS facial appearance" although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.

Insight into the mechanisms and consequences of recurrent telomere capture associated with a sub-telomeric deletion.

A complex mosaicism of the short arm of chromosome 1 detected by SNP microarray analysis is described in a patient presenting a 4-Mb 1p36 terminal deletion and associated phenotypic features. The array pattern of chromosome 1p displayed an intriguing increase in divergence of the SNP heterozygote frequency from the expected 50% from the centromere towards the 1p36 breakpoint. This suggests that various overlapping segments of UPD were derived by somatic recombination between the 1p homologues. The most likely explanation was the occurrence of a series of events initiated in either a gamete or an early embryonic cell division involving a 1pter deletion rapidly followed by multiple telomere captures, resulting in additive, stepped increases in frequency of homozygosity towards the telomere. The largest segment involved the entire 1p, and at least four other capture events were observed, indicating that at least five independent telomere captures occurred in separate cell lineages. The determination of breakpoint position by detection of abrupt changes in B-allele frequency using a moving window analysis demonstrated that they were identical in blood and saliva, the tissues available for analysis. We developed a model to explain the interaction of parameters determining the mosaic clones and concluded that, while number, size, and position of telomere captures were important initiating determinants, variation in individual clone frequencies was the main contributor to mosaic differences between tissues. All previous reports of telomere capture have been restricted to single events. Other cases involving multiple telomere capture probably exist but require investigation by SNP microarrays for their detection.

Neurons derived from induced pluripotent stem cells on microelectrode arrays: a human model for neurodevelopmental disorders

Neurons derived from induced pluripotent stem cells on microelectrode arrays: a human model for neurodevelopmental disorders

Clinical application of SNP array analysis in fetuses with ventricular septal defects and normal karyotypes.

The present study aims to evaluate the utility of high-resolution single-nucleotide polymorphism (SNP) arrays in fetuses with ventricular septal defects (VSDs) with or without other structural anomalies but with normal karyotypes and to investigate the outcomes of cases of prenatal VSDs via clinical follow-up. We analyzed 144 fetuses with VSDs and normal karyotypes using Affymetrix CytoScan HD arrays and the analyses were carried out a year after birth. Clinically significant CNVs were detected in 12 fetuses (8.3%). The most common pathogenic CNV was a 22q11.2 deletion with a detection rate of 2.8% (4/144). Well-known microdeletion or microduplication syndromes, including Smith-Magenis, Miller-Dieker, 9q subtelomeric deletion, 1p36 microdeletion, 1q21.1 microduplication, and terminal 4q deletion syndrome, were identified in six cases. Three regions of chromosomal imbalance were also identified: microduplication at 12q24.32q24.33, microdeletion at 16p13.13p13.12 and microdeletion at Xp21.1. The genes TBX1, SKI, GJA5, EHMT1, NOTCH1 were identified as established genes and LZTR1, PRDM26, YWHAE, FAT1, AKAP10, ERCC4, and ULK1 were identified as potential candidate genes of fetal VSDs. There was no significant difference in pathogenic CNVs between isolated VSDs and VSDs with additional structural abnormalities. Ninety-five (74.8%) pregnant women with fetuses with benign CNVs chose to continue the pregnancy and had a favorable prognosis, while nine (75%) pregnant women with fetuses with pathogenic CNVs chose to terminate the pregnancy. High-resolution SNP arrays are valuable tools for identifying submicroscopic chromosomal abnormalities in the prenatal diagnosis of VSDs. An excellent outcome can be expected for VSD fetuses that are negative for chromosomal anomalies and other severe anatomic abnormalities.

6p25 Deletion and Anesthetic Implications During Growing Rod Insertion for Early Onset Scoliosis

6p25 is a rare yet clinically identifiable disorder that results from the deletion of the short arm of chromosome 6. Due to the craniofacial, central nervous system, renal, cardiac, and skeletal abnormalities, anesthetic care may be required during various surgical interventions. The associated structural anomalies and end-organ involvement may impact the perioperative care. We present a 4-year-old girl with subtelomeric 6p25 deletion who required anesthetic care during placement of growing rods to treat progressive scoliosis. A review of literature was performed, the end-organ involvement was discussed, and options for anesthetic care were presented. J Med Cases. 2017;8(3):73-76 doi: https://doi.org/10.14740/jmc2748w

6p25 Deletion and Anesthetic Implications During Growing Rod Insertion for Early Onset Scoliosis

6p25 is a rare yet clinically identifiable disorder that results from the deletion of the short arm of chromosome 6. Due to the craniofacial, central nervous system, renal, cardiac, and skeletal abnormalities, anesthetic care may be required during various surgical interventions. The associated structural anomalies and end-organ involvement may impact the perioperative care. We present a 4-year-old girl with subtelomeric 6p25 deletion who required anesthetic care during placement of growing rods to treat progressive scoliosis. A review of literature was performed, the end-organ involvement was discussed, and options for anesthetic care were presented. J Med Cases. 2017;8(3):73-76 doi: https://doi.org/10.14740/jmc2748w

Increased first-trimester nuchal translucency associated with a dicentric chromosome and 9q34.3 microdeletion syndrome

We present prenatal diagnosis and chromosomal microarray analysis (CMA) of 9q34.3 microdeletion in a foetus with an increased nuchal translucency (NT). Conventional G-banding analysis showed a de novo translocation: 45, XX, dic (9;13)(q34;p13). CMA revealed a 3.6 Mb 9q34.3 microdeletion encompassing an OMIM gene of EHMT1 consistent with the diagnosis of Kleefstra syndrome and 9q subtelomeric deletion syndrome. We suggest an application of CMA at prenatal diagnosis in pregnancies with increased NT and an apparent balanced translocation on conventional karyotype.

Subtelomeric Copy Number Variations: The Importance of 4p/4q Deletions in Patients with Congenital Anomalies and Developmental Disability

The most prevalent structural variations in the human genome are copy number variations (CNVs), which appear predominantly in the subtelomeric regions. Variable sizes of 4p/4q CNVs have been associated with several different psychiatric findings and developmental disability (DD). We analyzed 105 patients with congenital anomalies (CA) and developmental and/or intellectual disabilities (DD/ID) using MLPA subtelomeric specific kits (P036 /P070) and 4 of them using microarrays. We found abnormal subtelomeric CNVs in 15 patients (14.3%), including 8 patients with subtelomeric deletions at 4p/4q (53.3%). Additional genomic changes were observed at 1p36, 2q37.3, 5p15.3, 5q35.3, 8p23.3, 13q11, 14q32.3, 15q11.2, and Xq28/Yq12. This indicates the prevalence of independent deletions at 4p/4q, involving PIGG, TRIML2, and FRG1. Furthermore, we identified 15 genes with changes in copy number that contribute to neurological development and/or function, among them CRMP1, SORCS2, SLC25A4, and HELT. Our results highlight the association of genes with changes in copy number at 4p and 4q subtelomeric regions and the DD phenotype. Cytogenomic characterization of additional cases with distal deletions should help clarifying the role of subtelomeric CNVs in neurological diseases.

Deletion 2q37 syndrome: Cognitive-behavioral trajectories and autistic features related to breakpoint and deletion size.

Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc.

Molecular and clinical analyses with neuropsychological assessment of a case of del(10)(q26.2qter) without intellectual disability: Genomic and transcriptomic combined approach and review of the literature.

Terminal deletion of the long arm of the chromosome 10 is a rare but well known abnormality, with a large phenotypic variability. Very few data are available about subtelomeric deletion 10q26 patients without intellectual disability. Herein, we report the case of a young adult with a classical 10q26.2qter deletion. She exhibited mainly short stature at birth and in childhood/adulthood without intellectual disability or behavioral problems. After clinical and neuropsychological assessments, we performed genomic array and transcriptomic analysis and compared our results to the data available in the literature. The patient presents a 6.525 Mb heterozygous 10q26.2qter deletion, encompassed 48 genes. Among those genes, DOCK1, C10orf90, and CALY previously described as potential candidate genes for intellectual disability, were partially or completed deleted. Interestingly, they were not deregulated as demonstrated by transcriptomic analysis. This allowed us to suggest that the mechanism involved in the deletion 10qter phenotype is much more complex that only the haploinsufficiency of DOCK1 or other genes encompassed in the deletion. Genomic and transcriptomic combined approach has to be considered to understand this pathogenesis. © 2016 Wiley Periodicals, Inc.

Molecular characterization of a novel ring 6 chromosome using next generation sequencing.

BackgroundKaryotyping is the gold standard cytogenetic method for detection of ring chromosomes. In this study we report the molecular characterization of a novel ring 6 (r6) chromosome in a six-year-old girl with severe mental retardation, congenital heart disease and craniofacial abnormalities.MethodsCytogenetic analysis was performed by conventional karyotyping. Molecular genetic analyses were performed using high-resolution chromosome microarray analysis (CMA) and next generation sequencing (NGS). OMIM, UCSC and PubMed were used as reference databases to determine potential genotype to phenotype associations.ResultsPeripheral blood and skin fibroblast karyotyping revealed the presence of a dominant cell line, 46,XX,(r6)(p25.3;q27) and a minor cell line 45,XX,-6. Molecular karyotyping using NGS identified 6p25.3 and 6q27 subtelomeric deletions of 1.78 Mb and a 0.56 Mb, respectively. Based on the known genes located within the r6 deletion interval 6q25.3-pter, genotype to phenotype association studies found compelling evidence to suggest that hemizygous expression of disease genes FOXC1, FOXF2, IRF4 and GMDS was the main underlying cause of the patient’s phenotype. We further speculate that the severity of the patient’s symptoms may have been exacerbated by low-level instability of the r6 chromosome.ConclusionThis is the first report of a novel r6 chromosome characterized at the molecular level using NGS.

Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome.

Kleefstra syndrome (KS; OMIM #610253), formerly known as the 9q subtelomeric deletion syndrome, is an autosomal dominant cause of intellectual disability (ID) characterized by hypotonia and facial dysmorphisms.(1,2) The cause of KS is attributed to haploinsufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene (OMIM *607001) located at chromosome 9q34.3 (i.e., distal long arm of chromosome 9), either by microdeletion or point mutation. EHMT1 encodes a histone H3 methyltransferase at position Lys-9 (H3K9).(1-3).

Cochlear implantation in a child with subtelomeric 1q deletion syndrome and Dandy–Walker malformation

Abstract Subtelomeric 1q deletion syndrome is a rare disorder characterized by severe mental and growth retardation, microcephaly, distinct facial features and corpus callosum abnormalities. Senserineural hearing loss is not common in this syndrome. We report a 2-year-old boy with subtelomeric 1q deletion syndrome presented with typical craniofacial abnormalities and bilateral senserineural hearing loss. Imaging revealed corpus callosum hypogenesis and Dandy-Walker malformation. Cochlear implantation was successfully undertaken using a transmastoid facial recess aproach. After 12-months post-implantation, good audiological outcomes were obtained. Cochlear implantation can be considered for hearing rehabilitation in patients with subtelomeric 1q deletion syndrome and Dandy-Walker malformation.

Delimitation of theEarliness per se D1(Eps-D1) flowering gene to a subtelomeric chromosomal deletion in bread wheat (Triticum aestivum)

Earliness per se (Eps) genes account for the variation in flowering time when vernalization and photoperiod requirements are satisfied. Genomics and bioinformatics approaches were used to describe allelic variation for 40 Triticum aestivum genes predicted, by synteny with Brachypodium distachyon, to be in the 1DL Eps region. Re-sequencing 1DL genes revealed that varieties carrying early heading alleles at this locus, Spark and Cadenza, carry a subtelomeric deletion including several genes. The equivalent region in Rialto and Avalon is intact. A bimodal distribution in the segregating Spark X Rialto single seed descent (SSD) populations enabled the 1DL QTL to be defined as a discrete Mendelian factor, which we named Eps-D1. Near isogenic lines (NILs) and NIL derived key recombinants between markers flanking Eps-D1 suggest that the 1DL deletion contains the gene(s) underlying Eps-D1. The deletion spans the equivalent of the Triticum monoccocum Eps-A (m) 1 locus, and hence includes MODIFIER OF TRANSCRIPTION 1 (MOT1) and FTSH PROTEASE 4 (FTSH4), the candidates for Eps-A (m) 1. The deletion also contains T. aestivum EARLY FLOWERING 3-D1 (TaELF3-D1) a homologue of the Arabidopsis thaliana circadian clock gene EARLY FLOWERING 3. Eps-D1 is possibly a homologue of Eps-B1 on chromosome 1BL. NILs carrying the Eps-D1 deletion have significantly reduced total TaELF3 expression and altered TaGIGANTEA (TaGI) expression compared with wild type. Altered TaGI expression is consistent with an ELF3 mutant, hence we propose TaELF3-D1 as the more likely candidate for Eps-D1. This is the first direct fine mapping of Eps effect in bread wheat.