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

Journal
Genes
ISSN
2073-4425
Date Issued
2021
Author(s)
Maria Gabriela Obregon
Victoria Huckstadt
Abel Gomez
Type
Resource Types::text::journal::journal article
Scopus ID
2-s2.0-85099653893
WoS ID
WOS:000610256900001
DOI
URL
URL Institutional Repository
Abstract
<jats:p>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.</jats:p>
Project(s)
Dataset(s)
Subjects
22q11

; 

2 deletion syndrome

; 

mtdna heteroplasmy

; 

congenital defects

; 

abnormalities, multiple

; 

adult

; 

child, preschool

; 

chromosome deletion

; 

chromosomes, human, pair 22

; 

digeorge syndrome

; 

dna, mitochondrial

; 

female

; 

genes, mitochondrial

; 

heteroplasmy

; 

humans

; 

male

; 

maternal inheritance

; 

palate

; 

mitochondrial dna

; 

mitochondrial dna

; 

adult

; 

article

; 

atherosclerosis

; 

cardiovascular risk

; 

chromosome deletion 22q11

; 

clinical article

; 

congenital heart disease

; 

controlled study

; 

dna sequence

; 

female

; 

gene deletion

; 

gene frequency

; 

genetic variation

; 

heteroplasmy

; 

human

; 

maternal inheritance

; 

mitochondrial haplogroup

; 

palate malformation

; 

phenotype

; 

phylogeny

; 

progeny

; 

chromosome 22

; 

chromosome deletion

; 

digeorge syndrome

; 

genetics

; 

male

; 

mitochondrial gene

; 

multiple malformation syndrome

; 

palate

; 

preschool child