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 Human-specific expansion of 22q11.2 low copy repeats

2020 ◽  
Author(s):  
Lisanne Vervoort ◽  
Nicolas Dierckxsens ◽  
Zjef Pereboom ◽  
Oronzo Capozzi ◽  
Mariano Rocchi ◽  
...  
Keyword(s):  
Human Genome ◽  
Human Evolution ◽  
Human Population ◽  
Structural Variation ◽  
Deletion Syndrome ◽  
Species Variation ◽  
Segmental Duplications ◽  
22Q11.2 Deletion ◽  
Low Copy Repeats ◽  
Human Specific

AbstractSegmental duplications or low copy repeats (LCRs) constitute complex regions interspersed in the human genome. They have contributed significantly to human evolution by stimulating neo- or sub-functionalization of duplicated transcripts. The 22q11.2 region carries eight LCRs (LCR22s). One of these LCR22s was recently reported to be hypervariable in the human population. It remains unknown whether this variability exists also in non-human primates. To assess the inter- and intra-species variability, we de novo assembled the region in non-human primates by a combination of optical mapping techniques. Orangutan carries three LCR22-mediated inversions of which one is the ancient haplotype since it is also present in macaque. Using fiber-FISH, lineage-specific differences in LCR22 composition were mapped. The smallest and likely ancient haplotype is present in the chimpanzee, bonobo and rhesus macaque. The absence of intra-species variation in chimpanzee indicates the LCR22-A expansion to be unique to the human population. Further, we demonstrate that LCR22-specific genes are expressed in both human and non-human primate neuronal cell lines and show expression of several primate LCR22 transcripts for the first time. The human-specificity of the expansions suggest an important role for the region in human evolution and adaptation.Author summaryLow copy repeats or segmental duplications are DNA segments composed of various subunits which are duplicated across the genome. Due to the high level of sequence identity between these segments, homologous regions can misalign, resulting in reciprocal deletions and duplications, classified as genomic disorders. These regions are subject to structural variation in the human population. We recently detected extreme structural variation in one of the most complex segmental duplication regions of the human genome, the low copy repeats on chromosome 22 (LCR22s). Rearrangements between the LCR22s result in the 22q11.2 deletion/duplication syndrome, the most common human genomic disorder. However, it remains unknown whether this variability is human-specific. In this study, we investigated those LCR22s in several individuals of the different great apes and macaque. We show only the smallest haplotype is present without any intra-species variation in the Pan genus, our closest ancestors. Hence, LCR22 expansions are human-specific, suggesting a role of these LCR22s in human evolution and adaptation and hypothesize the region contributes to the 22q11.2 deletion syndrome inter-patient phenotypic variability.

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 Incidental finding of APC deletion in a child: double trouble or double chance? – a case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Erica Rosina ◽  
Berardo Rinaldi ◽  
Rosamaria Silipigni ◽  
Luca Bergamaschi ◽  
Giovanna Gattuso ◽  
...  
Keyword(s):  
De Novo ◽  
22Q11.2 Deletion Syndrome ◽  
Copy Number Variations ◽  
Velopharyngeal Insufficiency ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
22Q11.2 Deletion ◽  
Poor Growth ◽  
Genome Wide ◽  
A Genome

Abstract Background 22q11.2 deletion syndrome is one of the most common genomic disorders, characterized by the variable presence of facial dysmorphisms, congenital cardiac defects, velopharyngeal insufficiency/cleft palate, thymic hypoplasia/aplasia, immunodeficiency, parathyroid hypoplasia, developmental delay, learning disabilities, psychiatric disorders, renal, ocular, and skeletal malformations, hearing loss and laryngeal abnormalities. Chromosomal microarray (CMA) hybridization is one of the most performed diagnostic tests but as a genome wide analysis, it can point out relevant incidental copy number variations. Case presentation We report the case of a 2-year-old boy that came to our attention for mild psychomotor delay, poor growth, and minor facial anomalies. Considering a diagnosis of 22q11.2 deletion syndrome, we performed CMA that not only confirmed our diagnosis, but also pointed out an additional de novo 5q21.3q22.2 microdeletion, encompassing APC gene. As a result of the genetic testing we enrolled the patient in a tailored surveillance protocol that enabled the early detection of a hepatoblastoma. The child underwent surgical and chemotherapic treatments with complete cancer eradication. Conclusions The concurrent finding of an expected result and an additional deletion of APC gene represents an example of a relevant issue about the health and ethical management of secondary findings revealed by genome-wide tests. Furthermore, this report highlights the need to develop dedicated surveillance guidelines for children with APC-related polyposis and raise the question whether to suspect and screen for APC-related conditions in cases of sporadic hepatoblastomas.

Sleep Disturbances in 22q11.2 Deletion Syndrome: A Case with Obstructive and Central Sleep Apnea

2007 ◽  
Vol 44 (3) ◽  
pp. 340-346 ◽  
Author(s):  
Carrie L. Heike ◽  
Anthony M. Avellino ◽  
Sohail K. Mirza ◽  
Yemiserach Kifle ◽  
Jonathan Perkins ◽  
...  
Keyword(s):  
Sleep Apnea ◽  
Sleep Disturbances ◽  
Phenotypic Variability ◽  
Central Sleep Apnea ◽  
22Q11.2 Deletion Syndrome ◽  
Obtuse Angle ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Mandibular Distraction Osteogenesis ◽  
Obstructive Sleep

The 22q11.2 deletion syndrome is characterized by wide phenotypic variability, frequently involving characteristic craniofacial features, cardiac malformations, and learning difficulties. Skeletal anomalies are also common and include an obtuse angle of the cranial base, retrognathia, and cervical spine abnormalities. Despite these anomalies, sleep-disturbed breathing is not reported frequently in patients with 22q11.2 deletion syndrome. We describe a patient with an obstructive sleep disturbance that was successfully treated with a tonsillectomy followed by mandibular distraction osteogenesis. She also had central sleep apnea, initially attributed to spinal cord impingement from cervical instability. Posterior cervical fusion was associated with a decrease in the number of central apneic events.

scholarly journals Diagnosis of 22q11.2 Deletion Syndrome in a Child With Congenital Heart Disease and Facial Dimorphism: A Case Report

2021 ◽  
Author(s):  
Natalia Dayane Moura Carvalho ◽  
Ronaldo Castillo Camargo ◽  
Heliana Maria Costa Garcia ◽  
Suely Regina da Silva Teles ◽  
Cleiton Fantin
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
22Q11.2 Deletion Syndrome ◽  
University Hospital ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Patient Reported ◽  
History Of ◽  
Low Copy Repeats

22q11.2 deletion syndrome is caused by a deletion in chromosome 22q11.2 and has more than 180 distinct phenotypes; however, no finding is pathognomonic or even mandatory. This syndrome can be diagnosed by fluorescence in situ hybridization. Thus, we report herein a patient from Manaus, Brazil, who has congenital heart disease and facial dimorphism with the presence of 22q11.2 deletion in the N25 region. Male patient, a 1-year-old son of non-consanguineous parents and without a family history of genetic disease. The patient was hospitalized in the cardiac intensive care unit of the Francisca Mendes University Hospital for surgery. The patient was diagnosed with interventricular communication, low atrial implantation, hypertelorism, and macroglossia. The FISH result revealed the presence of a proximal deletion in the N25 region (22q11.2) in only one of the pairs in chromosome 22. This finding revealed a diagnosis of 22q11.2 deletion syndrome, in other words, a hemizygotes deletion with haploinsufficiency of the CLTCL1 gene in this region. However, it is valid to say that the CLTCL1 gene is related to the clinical picture of the patient reported in this study. Cytogenetic analysis was essential for the etiological diagnosis and revealed 22q11.2 deletion in the N25 region, which resulted in 22q11.2 deletion syndrome. The importance of diagnosing this syndrome lies in the best therapeutic conduct, thus allowing a better quality of life for the patient and adequate genetic counseling. Other cytogenetic studies are essential in order to elucidate the size of the deletion and low copy repeats involved in this deletion.

scholarly journals Ontogeny of the facial phenotypic variability in Mexican patients with 22q11.2 deletion syndrome

2019 ◽  
Vol 15 (1) ◽  
Author(s):  
Arodi Farrera ◽  
María Villanueva ◽  
Alfredo Vizcaíno ◽  
Patricia Medina-Bravo ◽  
Norma Balderrábano-Saucedo ◽  
...  
Keyword(s):  
Medical Condition ◽  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Postnatal Ontogeny ◽  
Facial Morphology ◽  
22Q11.2 Deletion ◽  
Large Variability ◽  
Shape And Size ◽  
Mexican Patients

Abstract Background 22q11.2 deletion syndrome is a medical condition that results from genomic loss at chromosome 22. Affected patients exhibit large variability that ranges from a severe condition to mild symptoms. In addition, the spectrum of clinical features differs among populations and even within family members. The facial features related to this syndrome are not an exception, and although part of its variation arises through development, few studies address this topic in order to understand the intra and inter-population heterogeneities. Here, we analyze the ontogenetic dynamics of facial morphology of Mexican patients with del22q11.2 syndrome. Methods Frontal facial photographs of 37 patients (mean age = 7.65 ± 4.21 SE) with del22q11.2DS and 200 control subjects (mean age = 7.69 ± 4.26 SE) were analyzed using geometric morphometric methods. Overall mean shape and size differences between patients and controls were analyzed, as well as differences in ontogenetic trajectories (i.e. development, growth, and allometry). Results We found that Mexican patients show typical traits that have been reported for the Caucasian population. Additionally, there were significant differences between groups in the facial shape and size when all the ontogenetic stages were considered together and, along ontogeny. The developmental and allometric trajectories of patients and controls were similar, but they differed in allometric scaling. Finally, patients and controls showed different growth trajectories. Conclusion The results suggest that the typical face of patients with del22q11.2DS is established prenatally; nonetheless, the postnatal ontogeny could influence the dysmorphology and its variability through size-related changes.

Implications of COMT and Subclinical Psychiatric Symptoms on the Phenotypic Variability of 22q11.2 Deletion Syndrome: A Transversal and Longitudinal Approach

2017 ◽  
Vol 41 (S1) ◽  
pp. S82-S83
Author(s):  
S. Guerrera ◽  
M. Armando ◽  
M. Pontillo ◽  
F. Papaleo ◽  
S. Vicari
Keyword(s):  
Negative Symptoms ◽  
Psychiatric Symptoms ◽  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Structured Interview ◽  
Deletion Syndrome ◽  
Psychotic Symptoms ◽  
22Q11.2 Deletion ◽  
Comt Polymorphism ◽  
The Impact

Introduction22q11.2 deletion syndrome (22q11.2DS) results from a hemizygous microdeletion on chromosome 22 and is characterized by phenotypic variability. Several studies have been conducted on the impact of COMT functional polymorphism in 22q11DS, suggesting that attenuated psychotic manifestations are frequent in children and adolescents and represent one of the strongest predictors for the onset of psychotic disorder.ObjectivesWe explored possible interaction between COMT polymorphism and subclinical psychiatric symptoms in a 22q11.2DS cohort of 42 participants aged 6 to 26 years: 17 hemizygosity for COMT-Met and 25 hemizygosity for COMT-Val.AimsTo analyse impact of COMT gene in 22q11DS and its related psychiatric correlates.MethodEach participant, genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism, underwent structured psychiatric and cognitive assessment. Analysis of positive and negative symptoms was performed by the structured interview for prodromal syndromes (SIPS). Finally, longitudinal data available in a subsample of 24 individuals were used to explore the developmental trajectories of psychotic symptoms one year later.ResultsThere was a significant positive correlation between COMT Val polymorphism and positive symptoms; at follow-up, no significant correlation were found between COMT polymorphism and psychiatric symptoms. No other significant differences were found between groups (Comt/Met-Comt/Val) on any other CBCL or QI score.ConclusionsCOMT and additional genes microdeleted might interact in the susceptibility to schizophrenia in 22q11.2DS: psychotic symptoms might result from an epistatic interaction with other genes. Moreover, gene-environment, in presence of genetic vulnerability could increase the risk of schizophrenia in 22q11DS.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 92
Author(s):  
Boris Rebolledo-Jaramillo ◽  
Maria Gabriela Obregon ◽  
Victoria Huckstadt ◽  
Abel Gomez ◽  
Gabriela M. Repetto
Keyword(s):  
Mitochondrial Dna ◽  
Permutation Test ◽  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
P Value ◽  
Incomplete Penetrance ◽  
Frequency Change ◽  
22Q11.2 Deletion ◽  
Mitochondrial Dna Heteroplasmy

Congenital heart disease (CHD) and palatal anomalies (PA), are among the most common characteristics of 22q11.2 deletion syndrome (22q11.2DS), but they show incomplete penetrance, suggesting the presence of additional factors. The 22q11.2 deleted region contains nuclear encoded mitochondrial genes, and since mitochondrial function is critical during development, we hypothesized that changes in the mitochondrial DNA (mtDNA) could be involved in the intrafamilial variability of CHD and PA in cases of maternally inherited 22q11.2DS. To investigate this, we studied the transmission of heteroplasmic mtDNA alleles in seventeen phenotypically concordant and discordant mother-offspring 22q11.2DS pairs. We sequenced their mtDNA and identified 26 heteroplasmic variants at >1% frequency, representing 18 transmissions. The median allele frequency change between a mother and her child was twice as much, with a wider distribution range, in PA discordant pairs, p-value = 0.039 (permutation test, 11 concordant vs. 7 discordant variants), but not in CHD discordant pairs, p-value = 0.441 (9 vs. 9). Only the variant m.9507T>C was considered to be pathogenic, but it was unrelated to the structural phenotypes. Our study is novel, yet our results are not consistent with mtDNA variation contributing to PA or CHD in 22q11.2DS. Larger cohorts and additional factors should be considered moving forward.

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