Genetic variations that cause skull-fusion disorders
During the first year of life, the human brain doubles in size, continuing to grow through adolescence. But sometimes, the loosely connected plates of a baby's skull fuse too early, a disorder known as craniosynostosis. It can also produce facial and skull deformities, potentially damaging a young brain.
A research team led by Rockefeller University President Richard P. Lifton, then at Yale University, has identified mutations responsible for a type of craniosynostosis that affects the suture running along the top of the skull. The work appears in eLife.
"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."
Richard P. Lifton PhD, Director, Rockefeller University Laboratory of Human Genetics and Genomics, a prior Howard Hughes Medical Institute investigator.
Lifton and his team at Yale, including John Persing MD, and colleagues in the Section of Plastic and Reconstructive Surgery, found rare mutations in one gene collaborate with common variants near a second gene to cause midline craniosynostosis.
This disorder is a unique example of how interaction between genes can contribute to disease.
Midline craniosynostosis occurs when the suture in front of/or behind the soft spot atop a baby's skull closes early. Early closure produces a ridge or other cranial distortions. In some cases, even neurological problems.
First author Andrew Timberlake, an MD - PhD student in Lifton's lab at Yale, used social media to recruit many of the 191 families who participated in this study.
By plotting inheritance of this disorder through families, the team noticed that craniosynostosis showed up unpredictably. Clearly something more than simple dominant/recessive inheritance was at play. When they sequenced the participants' protein-coding genes, exomes, mutations in the SMAD6 gene caught their attention.
SMAD6 is a protein that inhibits so-called BMP signals, which promote bone formation. But not everyone carrying a rare SMAD6 mutation had midline craniosynostosis. In fact, none of the parents who shared the SMAD6 mutation with their affected children had a history of craniosynostosis — a finding that initially surprised researchers.
The team then looked to find mutations that might affect the same bone formation pathway. Previous research implicated common changes near the BMP2 gene, so they looked for skull suture variations among those families.
"It was amazing to find that affected children had inherited both the SMAD6 mutation and a common BMP2 variant.
"In each case, the SMAD6 mutation came from one parent and the BMP2 risk variant from the other, explaining why neither parent had craniosynostosis."
Andrew Timberlake MD PhD student, Lifton laboratory, Yale University.
Researchers believe risk variants located near BMP2 increase bone-promoting BMP signals, amplified due to the loss of SMAD6 and its ability to inhibit them. This resulted in a gap between skull bones, or fusing ahead of schedule.
Among the families studied, those who carried the rare, damaging SMAD6 mutation along with a common BMP2 risk variant always had midline craniosynostosis. But, those with only a SMAD6 mutation, and no BMP2 risk allele, were much less likely to suffer the disorder. This knowledge should help doctors and genetic counselors better assess risk within families.
Researchers suggest that a similar dynamic may play in other rare genetic disorders that don't appear to follow classical Mendelian inheritance patterns.
"Our results offer a clear demonstration of the interaction between rare and common variants, 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?""
Richard P. Lifton PhD
Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP - induced osteoblast differentiation (P < 10-20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.
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