Abstract 24: Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and Common BMP2 Alleles
نویسندگان
چکیده
Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 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.
منابع مشابه
De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the g...
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PURPOSE: Non-syndromic sagittal and/or metopic craniosynostosis, occurring once in every 4,000 live births, accounts for half of all craniosynostosis cases. Despite success in identifying the genes underlying rare syndromic craniosynostoses, mutations in these genes are very rarely found in their non-syndromic counterparts. We considered that the often sporadic occurrence of non-syndromic crani...
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This study aimed to investigate the contribution of four common DFNB (“DFN” for deafness and “B” for autosomal resessive locus) loci and GJB2 gene mutations (exon 2) in hearing impairment in individuals living in Markazi and Qom provinces of Iran. Forty consanguineous Iranian families with at least three affected individuals in family or pedigree who suffer from an autosomal recessive non-syndr...
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متن کاملGenetic analysis of non-syndromic craniosynostosis.
Craniosynostosis is a common malformation occurring in 3-5 per 10,000 live births. Most often craniosynostosis occurs as an isolated (i.e. non-syndromic) anomaly. Non-syndromic craniosynostosis (NSC) is a clinically and genetically heterogeneous condition that has the characteristics of a multifactorial trait. It is believed that each sutural synostosis (e.g. sagittal, coronal) represents a dif...
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عنوان ژورنال:
دوره 5 شماره
صفحات -
تاریخ انتشار 2016