Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome
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,...
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doaj-6c97ffa42d78431ca1c77e211edfbd762021-01-14T00:02:05ZengMDPI AGGenes2073-44252021-01-0112929210.3390/genes12010092Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion SyndromeBoris Rebolledo-Jaramillo0Maria Gabriela Obregon1Victoria Huckstadt2Abel Gomez3Gabriela M. Repetto4Center for Genetics and Genomics, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7710162, ChileServicio de Genética, Hospital de Pediatría Garrahan, Buenos Aires C1249ABP, ArgentinaServicio de Genética, Hospital de Pediatría Garrahan, Buenos Aires C1249ABP, ArgentinaServicio de Genética, Hospital de Pediatría Garrahan, Buenos Aires C1249ABP, ArgentinaCenter for Genetics and Genomics, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7710162, ChileCongenital 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, <i>p</i>-value = 0.039 (permutation test, 11 concordant vs. 7 discordant variants), but not in CHD discordant pairs, <i>p</i>-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.https://www.mdpi.com/2073-4425/12/1/9222q11.2 deletion syndromemtDNA heteroplasmycongenital defects |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Boris Rebolledo-Jaramillo Maria Gabriela Obregon Victoria Huckstadt Abel Gomez Gabriela M. Repetto |
spellingShingle |
Boris Rebolledo-Jaramillo Maria Gabriela Obregon Victoria Huckstadt Abel Gomez Gabriela M. Repetto Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome Genes 22q11.2 deletion syndrome mtDNA heteroplasmy congenital defects |
author_facet |
Boris Rebolledo-Jaramillo Maria Gabriela Obregon Victoria Huckstadt Abel Gomez Gabriela M. Repetto |
author_sort |
Boris Rebolledo-Jaramillo |
title |
Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome |
title_short |
Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome |
title_full |
Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome |
title_fullStr |
Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome |
title_full_unstemmed |
Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome |
title_sort |
contribution of mitochondrial dna heteroplasmy to the congenital cardiac and palatal phenotypic variability in maternally transmitted 22q11.2 deletion syndrome |
publisher |
MDPI AG |
series |
Genes |
issn |
2073-4425 |
publishDate |
2021-01-01 |
description |
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, <i>p</i>-value = 0.039 (permutation test, 11 concordant vs. 7 discordant variants), but not in CHD discordant pairs, <i>p</i>-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. |
topic |
22q11.2 deletion syndrome mtDNA heteroplasmy congenital defects |
url |
https://www.mdpi.com/2073-4425/12/1/92 |
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