Supplementary Note
There are 29 genes, three of which code for uncharacterized proteins, in the ~593 kb
segment flanked by the segmental duplications on 16p11.2 (Supplementary Table 1). As both
deletion and duplication of this region are sometimes associated with an abnormal phenotype,
some of these genes are likely dosage-sensitive. Candidate genes in this segment and their
expression patterns have been described elsewhere1-5. A majority of these genes has brain
expression, some of which have been shown to alter synaptic function, behavior, and memory
when knocked out in animals (MAP3K, DOC2A, SEZ6L2)1,4. Another gene of interest,
especially when considering the three cases here with aortic and/or aortic valve abnormalities
and the twins previously reported with bicuspid aortic valves, is HIRIP3, which encodes a
protein that interacts with HIRA and acts as a chromatin/histone modifier2. HIRA is deleted in
the 22q11.2 deletion syndrome, and it is a candidate for some of the features of that syndrome6.
Another parallel to the 22q11.2 deletion syndrome comes from the MAP kinase pathway. Mouse
models have suggested that there may be altered ERK1/2 (MAPK3/MAPK1) signaling in this
deletion syndrome7. Additionally, hemizygous deletions of MAPK1 in humans have resulted in a
phenotype similar to the 22q11.2 deletion syndrome8. Patients with the 16p11.2 microdeletion
lack one copy of MAPK3. While mouse studies have shown that MAPK1 is necessary for
survival, and MAPK3 is not9, this haploinsufficiency could be part of an additive affect
impacting pathways that are also partially disrupted in 22q11.2 deletion syndrome. Two other
genes within this 16p11.2 interval have been shown to be involved in another MAP kinase
pathway, the JNK1/2/3 pathway. Mouse experiments have shown that JNK1/2/3 are involved in
neuronal cell death and likely normal brain development9. Both PPP4C and TAOK2, within
16p11.2, are involved in JNK signaling10,11. Considering that the 16p11.2 microdeletion and
microduplication could be impacting multiple pathways that are important in brain development,
a possible explanation for the neurodevelopmental phenotype seen in these patients could be a
cumulative effect of abnormal dosage of several genes in the region.
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