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

ABSTRACT 22q11.2 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.