scholarly journals The 22q11 low copy repeats are characterized by unprecedented size and structure variability

2018 ◽  
Author(s):  
Wolfram Demaerel ◽  
Yulia Mostovoy ◽  
Feyza Yilmaz ◽  
Lisanne Vervoort ◽  
Steven Pastor ◽  
...  
Keyword(s):  
De Novo ◽  
Phenotypic Variability ◽  
Chromosomal Rearrangements ◽  
Deletion Syndrome ◽  
Genomic Disorder ◽  
Genome Variability ◽  
Low Copy Repeats ◽  
Different Populations ◽  
High Level

Abstract:Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The chromosome 22 LCRs (LCR22s) are amongst the most complex regions in the genome and their structure remains unresolved. These LCR22s mediate non-allelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS), causing the most frequent genomic disorder. Using fiber FISH optical mapping, we have de novo assembled the LCR22s in 33 cell lines. We observed a high level of variation in LCR22 structures, including 26 different haplotypes of LCR22A with alleles ranging from 250 Kb to over 2,000 Kb. An additional four haplotypes were detected using Bionano mapping. Further, Bionano maps generated from 154 individuals from different populations suggested significantly different LCR22 haplotype frequencies between populations. Furthermore, haplotype analysis in nine 22q11DS patients resulted in the localization of the NAHR site to a 160 Kb paralog between LCR22A and –D in seven patients and to a 31 Kb region in two individuals with a rearrangement between LCR22A and –B.. This 31 Kb region contains a palindromic AT-rich repeat known to be a driver of chromosomal rearrangements. Our study highlights an unprecedented level of polymorphism in the structure of LCR22s, which are likely still evolving. We present the most comprehensive map of LCR22 variation to date, paving the way towards investigating the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability in 22q11DS patients as well as in the general population.

scholarly journals 22q11.2 Low Copy Repeats Expanded in the Human Lineage

2021 ◽  
Vol 12 ◽  
Author(s):  
Lisanne Vervoort ◽  
Nicolas Dierckxsens ◽  
Zjef Pereboom ◽  
Oronzo Capozzi ◽  
Mariano Rocchi ◽  
...  
Keyword(s):  
Human Population ◽  
De Novo ◽  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Species Variation ◽  
Human Lineage ◽  
22Q11.2 Deletion ◽  
Functional Studies ◽  
Low Copy Repeats

Segmental duplications or low copy repeats (LCRs) constitute duplicated regions interspersed in the human genome, currently neglected in standard analyses due to their extreme complexity. Recent functional studies have indicated the potential of genes within LCRs in synaptogenesis, neuronal migration, and neocortical expansion in the human lineage. One of the regions with the highest proportion of duplicated sequence is the 22q11.2 locus, carrying eight LCRs (LCR22-A until LCR22-H), and rearrangements between them cause the 22q11.2 deletion syndrome. The LCR22-A block was recently reported to be hypervariable in the human population. It remains unknown whether this variability also exists in non-human primates, since research is strongly hampered by the presence of sequence gaps in the human and non-human primate reference genomes. To chart the LCR22 haplotypes and the associated inter- and intra-species variability, we de novo assembled the region in non-human primates by a combination of optical mapping techniques. A minimal and likely ancient haplotype is present in the chimpanzee, bonobo, and rhesus monkey without intra-species variation. In addition, the optical maps identified assembly errors and closed gaps in the orthologous chromosome 22 reference sequences. These findings indicate the LCR22 expansion to be unique to the human population, which might indicate involvement of the region in human evolution and adaptation. Those maps will enable LCR22-specific functional studies and investigate potential associations with the phenotypic variability in the 22q11.2 deletion syndrome.

scholarly journals The effect of Health Literacy on COVID-19 Vaccine Hesitancy: The Moderating Role of Stress

2021 ◽  
Author(s):  
Fan Zhang ◽  
Huiqiao Zhang ◽  
Yue Li ◽  
Sihui Peng ◽  
Yue Jiang ◽  
...  
Keyword(s):  
Health Literacy ◽  
Online Survey ◽  
High Stress ◽  
Vaccine Hesitancy ◽  
The People ◽  
Different Populations ◽  
Promotion Strategies ◽  
High Level ◽  
Moderating Role

Abstract Background The COVID-19 vaccine is an essential means to establish group immunity and prevent the spread of the pandemic. However, the public's hesitation has created major difficulties to the promotion of the vaccine. By investigating the relationship between health literacy and COVID-19 vaccine hesitancy, as well as the potential moderating role of stress, the present study would provide critical insights for tailoring vaccine-promotion strategies. Objective The two-fold research purpose is: i) address the effect of health literacy on people's attitude toward COVID-19 vaccine, ii) clarify the role of stress in this effect. Method With structured questionnaires, an online survey was conducted to evaluate general public's COVID-19 vaccine hesitancy, health literacy, and perceived stress. In total, 560 responses were collected, and moderated regression analysis was conducted to test the effect of health literacy on vaccine hesitancy among people with different levels of stress. Results A total of 560 participants aged over 18 years were included in this study. About 39.8% of the respondents reported vaccine hesitancy, and this rate is higher among those aged 20-30 years old (83%) and female (71.3%). The results showed people with higher level of health literacy are less likely to have vaccine hesitancy . However, this effect was only among those with lower to moderate level of stress , among the people with high stress, no significant effect of health literacy was found . Conclusions By focusing on the effect of health literacy on COVID-19 vaccine hesitancy, the findings showed education program increasing individual's health literacy may also effectively reduce the public's vaccine hesitancy and promote accepting attitude. However, for people with high level of stress, other health programs need to be developed to enhance their positive attitude toward the COVID-19 vaccine. In conclusion, promotion strategies should be tailored for different populations, with considering individual factors such as health literacy and stress. Keywords vaccine hesitancy; health literacy; stress; moderation

scholarly journals A novel 14q13.1–21.1 deletion identified by CNV-Seq in a patient with brain-lung-thyroid syndrome, tooth agenesis and immunodeficiency

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuyun Hu ◽  
Jun Liu ◽  
Ruolan Guo ◽  
Jun Guo ◽  
Zhipeng Zhao ◽  
...  
Keyword(s):  
De Novo ◽  
Deletion Syndrome ◽  
Tooth Agenesis ◽  
Diagnostic Strategy ◽  
Genomic Disorder ◽  
Case Presentation ◽  
Whole Exome ◽  
Number Variation ◽  
Phenotype Heterogeneity ◽  
Genomic Disorders

Abstract Background Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder. The phenotype heterogeneity depends on the deletion size, breakpoints and genes deleted. Critical genes like FOXG1, NKX2–1, PAX9 were identified. Case presentation We performed whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) for a patient with mild speech and motor developmental delay, short stature, recurrent pulmonary infections, tooth agenesis and triad of brain-lung-thyroid syndrome. By using CNV-seq, we identified a 3.1 Mb de novo interstitial deletion of the 14q13.2q21.1 region encompassing 17 OMIM genes including NKX2–1, PAX9 and NFKBIA. Our patient’s phenotype is consistent with other published 14q13 deletion patients. Conclusion Our results showed the combination of WES and CNV-seq is an effective diagnostic strategy for patients with genetic or genomic disorders. After reviewing published patients, we also proposed a new critical region for 14q13 deletion syndrome with is a more benign disorder compared to 14q11-q22 deletion syndrome.

The effect of Health Literacy on COVID-19 Vaccine Hesitancy: The Moderating Role of Stress (Preprint)

2021 ◽  
Author(s):  
Fan Zhang ◽  
Yue Li ◽  
Sihui Peng ◽  
Yue Jiang ◽  
Huihui Jin ◽  
...  
Keyword(s):  
Health Literacy ◽  
Online Survey ◽  
High Stress ◽  
Vaccine Hesitancy ◽  
The People ◽  
Different Populations ◽  
Promotion Strategies ◽  
High Level ◽  
Moderating Role

BACKGROUND The COVID-19 vaccine is an essential means to establish group immunity and prevent the spread of the pandemic. However, the public’s hesitation has created major difficulties to the promotion of the vaccine. By investigating the relationship between health literacy and COVID-19 vaccine hesitancy, as well as the potential moderating role of stress, the present study would provide critical insights for tailoring vaccine-promotion strategies. OBJECTIVE The two-fold research purpose is: i) address the effect of health literacy on people’s attitude toward COVID-19 vaccine, ii) clarify the role of stress in this effect. METHODS With structured questionnaires, an online survey was conducted to evaluate general public’s COVID-19 vaccine hesitancy, health literacy, and perceived stress. In total, 560 responses were collected, and moderated regression analysis was conducted to test the effect of health literacy on vaccine hesitancy among people with different levels of stress. RESULTS A total of 560 participants aged over 18 years were included in this study. About 39.8% of the respondents reported vaccine hesitancy, and this rate is higher among those aged 20-30 years old (83%) and female (71.3%). The results showed people with higher level of health literacy are less likely to have vaccine hesitancy (β = -2.00, 95%CI= [-3.00~ -0.99]). However, this effect was only among those with lower to moderate level of stress (β =-3.43, p<0.001), among the people with high stress, no significant effect of health literacy was found (β =-0.53, p>0.05). CONCLUSIONS By focusing on the effect of health literacy on COVID-19 vaccine hesitancy, the findings showed education program increasing individual’s health literacy may also effectively reduce the public’s vaccine hesitancy and promote accepting attitude. However, for people with high level of stress, other health programs need to be developed to enhance their positive attitude toward the COVID-19 vaccine. In conclusion, promotion strategies should be tailored for different populations, with considering individual factors such as health literacy and stress.

Aetiology, genes, and environment

ESC CardioMed ◽  
2018 ◽  
pp. 742-746
Author(s):  
Elisavet Fotiou ◽  
Bernard Keavney
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Recurrence Risk ◽  
Copy Number Variations ◽  
Deletion Syndrome ◽  
Clinical Genetics ◽  
Single Nucleotide ◽  
Neurodevelopmental Delay ◽  
Substantial Progress ◽  
Neurodevelopmental Abnormalities

Genetic factors predisposing to congenital heart disease (CHD) are characterized by extreme heterogeneity, comprising changes to the genome at all levels of variation from chromosomal aneuploidy to single nucleotide mutations. About 15–20% of patients with CHD have underlying genetic causes identifiable by currently standard clinical genetics laboratory testing, including patients with Down syndrome, Turner syndrome, 22q11 deletion syndrome, other chromosomal rearrangements, and multisystem conditions mediated by single nucleotide changes in particular genes (e.g. Noonan’s syndrome). Extracardiac malformations and/or neurodevelopmental abnormalities characteristic of these conditions are important diagnostic cues. Mendelian families with isolated non-syndromic CHD are very rare. In the remaining 80% of cases, CHD is apparently ‘sporadic’ and the empirical recurrence risk to a sibling of an index case in such families is approximately 3%. This low recurrence risk suggests that de novo events, that is, new mutations in affected offspring absent in the parents, are an important potential genetic cause of CHD. De novo copy number variations such as 1q21.1 duplication have been shown to contribute to aetiology in 5–10% of apparently sporadic patients. Recent studies have also shown that approximately 20% of patients without recognized syndromic presentations, but with CHD accompanied by extracardiac malformations and/or neurodevelopmental delay, may have pathogenic de novo single nucleotide changes discoverable by exome sequencing. Continuing advances in genomic technologies present the prospect of substantial progress in the understanding of the genetic predisposition to CHD, but further research in large cohort studies is required.

scholarly journals Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

2017 ◽  
Vol 55 (3) ◽  
pp. 205-213 ◽  
Author(s):  
Solveig Heide ◽  
Sandra Chantot-Bastaraud ◽  
Boris Keren ◽  
Madeleine D Harbison ◽  
Salah Azzi ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Paternal Allele ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Phenotype Correlation ◽  
Growth Disturbance ◽  
Correlation Studies ◽  
Functional Consequences

BackgroundThe 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.ObjectivesTo report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.MethodsFrom a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.ResultsLarge duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C.ConclusionsThe phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

scholarly journals Unusual de novo Partial Trisomy 17p12p11.2 due to Unbalanced Insertion into 5p13.1 in a Severely Affected Boy

2017 ◽  
Vol 06 (03) ◽  
pp. 165-168 ◽  
Author(s):  
Luis Mendez-Rosado ◽  
Araceli Lantigua ◽  
Juan Galarza ◽  
Ahmed Hamid Al-Rikabi ◽  
Monika Ziegler ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Partial Trisomy ◽  
Derivative Chromosome ◽  
Genomic Disorder ◽  
Charcot Marie Tooth Disease ◽  
Dysmorphic Features ◽  
Copy Numbers ◽  
Tooth Disease

AbstractGain of copy numbers can be due to different chromosomal rearrangements such as direct or indirect duplications, translocations, small supernumerary marker chromosomes, or insertions. In a 3-year-old boy with dysmorphic features and developmental delay, chromosome analyses revealed a derivative chromosome 5. Microdissection and reverse fluorescence in situ hybridization identified the in 5p13.1 inserted part as 17p12-p11.2 material. Thus the patient suffered from a rare combination of genomic disorder, that is, Charcot-Marie-Tooth disease type 1A and Potocki-Lupski syndrome. Parental studies indicated that the abnormality was de novo in origin. As the question how this rearrangement arose cannot be answered conclusively, formal genetic counseling is warranted, which includes a discussion regarding the possibility of gonadal mosaicism. In conclusion, this case highlights that chromosome 17p is genetically relatively instable, and thus it can lead to rare chromosomal conditions.

Partial 5p Deletion and Partial 5q Duplication in a Patient with Multiple Congenital Anomalies: A Two-Step Mechanism in Chromosomal Rearrangement Mediated by Non-Allelic Homologous Recombination

2018 ◽  
Vol 156 (2) ◽  
pp. 65-70
Author(s):  
Zhishuo Z. Ou ◽  
Sally Kochmar ◽  
Svetlana A. Yatsenko ◽  
Audrey C. Woerner ◽  
Roxanne Acquaro ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
De Novo ◽  
Chromosome Analysis ◽  
Bioinformatic Analysis ◽  
Deletion Syndrome ◽  
Fish Analysis ◽  
Feeding Difficulties ◽  
Low Copy Repeats ◽  
5P Deletion ◽  
Nonallelic Homologous Recombination

We describe a 5-month-old female who presented with clinical features of 5p deletion syndrome, including high-pitched cry, microcephaly, micrognathia, bilateral preauricular tags, bifid uvula, abnormal palmar creases, bilateral hypoplastic nipples, feeding difficulties, and developmental delay. In addition, the patient also had a cardiac defect, proximal esophageal atresia, and distal tracheoesophageal fistula. aCGH of the patient revealed a 22.9-Mb deletion of chromosome 5p15.33p14.3 and an 8.28-Mb duplication of chromosome 5q12.1q13.2. Parental chromosome analysis indicated that these alterations are de novo. Chromosome and FISH analysis demonstrated that the 5q12.1q13.2 duplicated segment was attached to the 5p14.3 region with the band 5q12.1 more distal to the centromere than the band 5q13.2. Based on the bioinformatic analysis, we postulate a mechanism for the formation of this complex rearrangement of chromosome 5 by 2-step-wise events mediate by nonallelic homologous recombination between low copy repeats. To the best of our knowledge this rearrangement found in our patient has not been reported in the literature. This report demonstrates the value of chromosome analysis in conjunction with FISH and aCGH for identification of complex rearrangements which cannot be revealed by array analysis alone.

A Novel 4q32.3 Deletion in a Boy: Additional Signs and the Role of MARCH1

2021 ◽  
Author(s):  
Xena Giada Pappalardo ◽  
Martino Ruggieri ◽  
Raffaele Falsaperla ◽  
Salvatore Savasta ◽  
Umberto Raucci ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Growth Failure ◽  
Deletion Syndrome ◽  
Comparative Genomic ◽  
Mild Developmental Delay ◽  
Uncommon Condition ◽  
Craniofacial Features ◽  
Adducted Thumbs ◽  
Genomic Variant

AbstractThe 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

Prenatal Diagnosis of 4q Terminal Deletion and Review of the Literature

2019 ◽  
Vol 158 (2) ◽  
pp. 63-73 ◽  
Author(s):  
Zsolt Tidrenczel ◽  
Erika P. Tardy ◽  
Henriett Pikó ◽  
Edina Sarkadi ◽  
Ildikó Böjtös ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
De Novo ◽  
Phenotypic Variability ◽  
Chromosome Analysis ◽  
Index Patient ◽  
Maternal Serum ◽  
Prenatal Ultrasound ◽  
Terminal Deletion ◽  
Deletion Syndrome ◽  
Comparative Genome Hybridization

Terminal deletion of chromosome 4 (4q deletion syndrome) is a rare genetic condition that is characterized by a broad clinical spectrum and phenotypic variability. Diagnosis of the distinct condition can be identified by conventional chromosome analysis and small deletions by novel molecular cytogenetic methods such as microarray comparative genome hybridization (aCGH). Prenatal diagnosis is challenging; to date 10 cases have been described. We report a prenatally diagnosed case of de novo 4q deletion syndrome confirmed by conventional karyotyping and FISH due to an elevated combined risk for Down syndrome and prenatal ultrasound findings. aCGH validated the diagnosis and offered exact characterization of the disorder. Cytogenetic and microarray results described a 4q32.1qter terminal deletion of the fetus. Prenatal ultrasound detected multiple nonstructural findings (micrognathia, choroid plexus cysts, echogenic fetal bowel, short femur, and cardiac axis deviation). Pregnancy was terminated at 20 weeks. In addition to the index patient, we reviewed the 10 prenatally published cases of 4q deletion syndrome in the literature and compared these with our results. We summarize the patients' characteristics and prenatal clinical findings. Alterations of maternal serum biochemical factors, an elevated combined risk for trisomies, and distinct ultrasonographic findings can often be observed in cases of prenatal 4q deletion syndrome and may facilitate the otherwise difficult prenatal diagnosis.

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