A catalog of hemizygous variation in 127 22q11 deletion patients

The 22q11.2 deletion syndrome is the most common microdeletion disorder, with wide phenotypic variability. To investigate variation within the non-deleted allele we performed targeted resequencing of the 22q11.2 region for 127 patients, identifying multiple deletion sizes, including two deletions with atypical breakpoints. We cataloged ~12,000 hemizygous variant positions, of which 84% were previously annotated. Within the coding regions 95 non-synonymous variants, three stop gains, and two frameshift insertions were identified, some of which we speculate could contribute to atypical phenotypes. We also catalog tolerability of 22q11 gene mutations based on related autosomal recessive disorders in man, embryonic lethality in mice, cross-species conservation and observations that some genes harbor more or less variants than expected. This extensive catalog of hemizygous variants will serve as a blueprint for future experiments to correlate 22q11DS variation with phenotype. Mapping the intact chromosomes of patients who have a partial chromosomal deletion may reveal gene function. Individuals with similar deletions of a small piece of chromosome 22, known as 22q11.2 deletion syndrome (22q11.2DS), can show remarkably variable symptoms, which include heart defects, facial differences, and learning difficulties. The differences might result from unmasking of various mutations in the intact segment. Joris Vermeesch at KU Leuven in Belgium and an international team of colleagues mapped the variation in the intact arm of chromosome 22 in 127 patients with 22q11.2DS. They identified almost 12,000 variant positions, including variants of 11 of the 18 genes in the region that have unknown functions. The catalogue of variation will help in matching mutations with symptoms to determine gene function.