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Rare, Common Variants Together Affect Skull Fusion Disorder in Infants

NEW YORK (GenomeWeb) – An epistatic interaction between a rare genetic variant and common genetic variants appears to lead to a skull-fusion disorder that affects infants, according to a new study.

The human brain doubles in size in the first year after birth and continues to grow through adolescence. But in some infants — about one in 2,000 — the skull plates fuse early. Such craniosynostosis can be treated surgically, but it can cause brain compression as well as facial and skull deformities.

A team of researchers from Yale University sequenced the exomes of 132 parent-offspring trios and additional probands and found a link between a rare variant in SMAD6 and non-syndromic midline craniosynostosis, as they reported in eLife this week. However, the researchers noted that the SMAD6 variant exhibited incomplete penetrance.

Previous work had also implicated common variants near BMP2 in craniosynostosis risk. The researchers deduced that those variants in combination with the SMAD6 mutation explained the inheritance pattern the researchers saw in their cohort: people with both the SMAD6 mutation and a common BMP2 risk variant all had midline craniosynostosis, while only a few people with just the SMAD6 variant did.

"While this discovery will immediately help us diagnose and counsel patients, it also has much broader relevance for understanding the genetics of complex traits, including many human diseases," Rockefeller University's Richard Lifton, then at Yale, said in a statement.

By sequencing the exomes of 191 probands, Lifton and his colleagues uncovered 144 de novo mutations. SMAD6 harbored three of thosemutations, two of which were loss-of-function mutations. In addition, two of these mutations were found in probands and one was uncovered in the unaffected mother of a proband. When the researchers expanded their scope to include transmitted mutations, they identified 13 rare heterozygous damaging variants in SMAD6.

SMAD6 is part of the inhibitory SMAD family, and it inhibits BMP signaling, which is involved in bone formation, including the closure of cranial sutures.

However, the researchers noted that SMAD6 mutations exhibited "striking" incomplete penetrance — none of the 10 parents who were SMAD6 mutation carriers had had craniosynostosis.

Instead, Lifton and his colleagues said that other genetic loci might be at work.

As a recent genome-wide association study had implicated loci near BMP2 in craniosynostosis risk, they examined whether these common risk alleles, particularly the rs1884302 risk allele, could account for that incomplete penetrance.

Fourteen people in their cohort had both the SMAD6 mutation and the rs1884302 risk allele and all of them had craniosynostosis, the researchers reported. Of the 16 people with the SMAD6 mutation, but not the rs1884302 risk allele, three had craniosynostosis, and none of the people with only the rs1884302 risk allele had craniosynostosis.

The researchers suspected that the common BMP2 variants increase the level of BMP signaling to intensify the loss of SMAD6's ability to inhibit signaling.

"It was amazing to then find that the affected children had inherited both the SMAD6 mutation and the common BMP2 variant," first author Andrew Timberlake, an MD-PhD student at Yale, said in a statement. "In each case, the SMAD6 mutation came from one parent and the BMP2 risk variant came from the other parent, explaining why neither parent had craniosynostosis."

Such an epistatic inheritance pattern might also be present in other rare genetic disorders, the researchers noted.

"Our results offer a clear demonstration of the interaction between rare and common variants," Lifton said, "offering one explanation to a lingering question in genetics: Why do some individuals with potent rare mutations develop disease, while others with the same mutations do not?"