@article {495,
	title = {Co-occurrence of frameshift mutations in  and  in a child with complex craniosynostosis.},
	journal = {Hum Genome Var},
	volume = {5},
	year = {2018},
	month = {2018},
	pages = {14},
	abstract = {<p>Non-syndromic craniosynostosis (CS) affects 1 in 2350 live births. Recent studies have shown that a significant fraction of cases are caused by de novo or rare transmitted mutations that promote premature osteoblast differentiation in cranial sutures. Rare heterozygous loss-of-function (LOF) mutations in  and  are highly enriched in patients with non-syndromic sagittal and coronal CS, respectively. Interestingly, both mutations show striking incomplete penetrance, suggesting a role for modifying alleles; in the case of , a common variant near  drastically increases penetrance of sagittal CS. Here, we report a proband presenting with both sagittal and coronal craniosynostosis with the highly unusual recurrence of CS within two months of initial surgery, requiring a second operation to re-establish suture patency at six months of age. Exome sequencing revealed a rare transmitted frameshift mutation in  (p. 152 fs*27) inherited from an unaffected parent, absence of the common  risk variant, and a de novo frameshift mutation in  (p.E548fs*14).  and  independently inhibit transcriptional targets of BMP signaling. The findings are consistent with epistasis of these mutations, increasing penetrance and severity of CS in this proband. They also add to the list of composite phenotypes resulting from two Mendelian mutations, and support the utility of exome sequencing in atypical CS cases.</p>},
	issn = {2054-345X},
	doi = {10.1038/s41439-018-0014-x},
	author = {Timberlake, Andrew T and Wu, Robin and Nelson-Williams, Carol and Furey, Charuta G and Hildebrand, Kristi I and Elton, Scott W and Wood, Jeyhan S and Persing, John A and Lifton, Richard P}
}
