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.

scholarly journals Contribution of mitochondrial DNA heteroplasmy to the phenotypic variability in maternally transmitted 22q11.2 deletion syndrome

2020 ◽  
Author(s):  
Boris Rebolledo-Jaramillo ◽  
Maria Gabriela Obregon ◽  
Victoria Huckstadt ◽  
Abel Gomez ◽  
Gabriela M. Repetto
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Congenital Defects ◽  
P Value ◽  
Frequency Change ◽  
22Q11.2 Deletion ◽  
Cardiac Phenotype ◽  
Significant Difference

ABSTRACT22q11.2 deletion syndrome (22q11DS) has an incidence of 1 in 4,000. Most cases occur de novo, but about 10–15% of cases are inherited. Features include congenital heart disease, cleft palate, developmental delay, and other characteristics that can vary even among family members. The presence of nuclear mitochondrial genes in the deleted region, and the requirement of mitochondrial function for proper embryonic development, suggests that intrafamilial variability in maternally transmitted 22q11DS could be explained, at least partially, by variation in mitochondrial DNA (mtDNA). Thus, we sequenced the mtDNA of seventeen 22q11DS mother-child pairs. We identified 29 heteroplasmic variants at the 1% level, and compared the intrafamilial allele frequency change between phenotypically concordant and discordant pairs. We observed a statistically significant difference for the palatal phenotype: p-value = 0.048 (permutation test, 8 concordant vs. 9 discordant pairs), but not for the cardiac phenotype: p-value = 0.568 (6 vs. 11).Mitochondrial function has been primarily studied in mouse models of neurological 22q11DS phenotypes. Our study sets a precedent for considering human mitochondrial variation as a genetic modifier of congenital defects in this syndrome, and although our results are limited by sample size, they suggest a role for mitochondrial variation in the palatal phenotype.

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.

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 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 Intergenerational and intrafamilial phenotypic variability in 22q11.2 Deletion syndrome subjects

2014 ◽  
Vol 15 (1) ◽  
Author(s):  
Emilia Cirillo ◽  
Giuliana Giardino ◽  
Vera Gallo ◽  
Pamela Puliafito ◽  
Chiara Azzari ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Intrafamilial Phenotypic Variability

scholarly journals Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome

Nucleus ◽  
2013 ◽  
Vol 4 (6) ◽  
pp. 487-493 ◽  
Author(s):  
Michael J Zeitz ◽  
Paula P Lerner ◽  
Ferhat Ay ◽  
Eric Van Nostrand ◽  
Julia D Heidmann ◽  
...  
Keyword(s):  
Long Range ◽  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Long Range Interactions

Scoliosis in association with the 22q11.2 deletion syndrome: an observational study

2018 ◽  
Vol 104 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Jelle F Homans ◽  
Vyaas G M Baldew ◽  
Rob C Brink ◽  
Moyo C Kruyt ◽  
Tom P C Schlösser ◽  
...  
Keyword(s):  
Medical Center ◽  
Phenotypic Variability ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Scoliotic Curve ◽  
Microdeletion Syndrome ◽  
Curve Pattern ◽  
22Q11.2 Deletion ◽  
Cross Sectional ◽  
Curve Patterns

ObjectiveThe 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. It is characterised by wide phenotypic variability, including congenital heart disease (CHD), immunodeficiency and scoliosis. However, little is known regarding the prevalence and characteristics of scoliosis in patients with 22q11.2DS. The objective of this study is to assess the prevalence of scoliosis, its characteristics and the association with CHD in patients with 22q11.2DS.DesignThis prevalence study is based on physical examination and questionnaires of the world’s largest 22q11.2DS longitudinal collected database (n=1393, Children’s Hospital of Philadelphia) and was augmented with the scoliosis prevalence based on radiography in a smaller cohort (cross-sectional, University Medical Center Utrecht).PatientsPatients with a laboratory-confirmed 22q11.2 deletion who visited the specialised outpatient clinics were considered for inclusion.Main outcome measures(1) The prevalence of scoliosis, (2) its association with CHD, and (3) the similarity between 22q11.2DS curve patterns and adolescent idiopathic scoliosis (AIS) curve patterns.ResultsWithin the Philadelphia cohort, the prevalence of scoliosis in patients older than 16 years (n=317) was 48% (n=152). A similar prevalence (49%) was shown for the younger Utrecht cohort (n=97). The occurrence of scoliosis was not associated with the presence of CHD. Sixty-three per cent of patients with scoliosis had a scoliotic curve pattern that resembled AIS.ConclusionsClinicians should be aware that scoliosis is highly prevalent (48%–49%) in association with 22q11.2DS, irrespective of other clinical features (eg, the presence of CHD). Furthermore, 22q11.2DS may provide insights into the causes of AIS.

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