@article {914, title = {Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.}, journal = {Nat Med}, volume = {26}, year = {2020}, month = {2020 11}, pages = {1754-1765}, abstract = {

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17\% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22\% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

}, keywords = {Brain, Cerebral Ventricles, Exome, Female, Genetic Predisposition to Disease, Humans, Hydrocephalus, Male, Mutation, Neural Stem Cells, Neurogenesis, Neuroglia, Transcription Factors, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Whole Exome Sequencing}, issn = {1546-170X}, doi = {10.1038/s41591-020-1090-2}, author = {Jin, Sheng Chih and Dong, Weilai and Kundishora, Adam J and Panchagnula, Shreyas and Moreno-De-Luca, Andres and Furey, Charuta G and Allocco, August A and Walker, Rebecca L and Nelson-Williams, Carol and Smith, Hannah and Dunbar, Ashley and Conine, Sierra and Lu, Qiongshi and Zeng, Xue and Sierant, Michael C and Knight, James R and Sullivan, William and Duy, Phan Q and DeSpenza, Tyrone and Reeves, Benjamin C and Karimy, Jason K and Marlier, Arnaud and Castaldi, Christopher and Tikhonova, Irina R and Li, Boyang and Pe{\~n}a, Helena Perez and Broach, James R and Kabachelor, Edith M and Ssenyonga, Peter and Hehnly, Christine and Ge, Li and Keren, Boris and Timberlake, Andrew T and Goto, June and Mangano, Francesco T and Johnston, James M and Butler, William E and Warf, Benjamin C and Smith, Edward R and Schiff, Steven J and Limbrick, David D and Heuer, Gregory and Jackson, Eric M and Iskandar, Bermans J and Mane, Shrikant and Haider, Shozeb and Guclu, Bulent and Bayri, Yasar and Sahin, Yener and Duncan, Charles C and Apuzzo, Michael L J and DiLuna, Michael L and Hoffman, Ellen J and {\v S}estan, Nenad and Ment, Laura R and Alper, Seth L and Bilguvar, Kaya and Geschwind, Daniel H and G{\"u}nel, Murat and Lifton, Richard P and Kahle, Kristopher T} } @article {724, title = {Mutations in and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {116}, year = {2019}, month = {2019 Jul 23}, pages = {15116-15121}, abstract = {

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15\% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation ( = 4.0 {\texttimes} 10); additionally, a rare damaging mutation in , which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in , a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant ( = 8.2 {\texttimes} 10). Three probands had rare damaging mutations in , , or , which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier , and , encoding catenin α-1. These findings establish as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

}, issn = {1091-6490}, doi = {10.1073/pnas.1902041116}, author = {Timberlake, Andrew T and Jin, Sheng Chih and Nelson-Williams, Carol and Wu, Robin and Furey, Charuta G and Islam, Barira and Haider, Shozeb and Loring, Erin and Galm, Amy and Steinbacher, Derek M and Larysz, Dawid and Staffenberg, David A and Flores, Roberto L and Rodriguez, Eduardo D and Boggon, Titus J and Persing, John A and Lifton, Richard P} } @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 = {

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.

}, 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} } @article {386, title = {De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 08 29}, pages = {E7341-E7347}, abstract = {

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 genetics of NSC is largely unexplored. More than 95\% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, = 2.4 {\texttimes} 10). had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10\% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near increased the penetrance of mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

}, keywords = {Adult, Animals, Bone Morphogenetic Proteins, Child, Child, Preschool, Cranial Sutures, Craniosynostoses, Exome, Female, Humans, Male, MAP Kinase Signaling System, Mutation, Osteogenesis, Penetrance, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction, Smad6 Protein, Whole Exome Sequencing}, issn = {1091-6490}, doi = {10.1073/pnas.1709255114}, author = {Timberlake, Andrew T and Furey, Charuta G and Choi, Jungmin and Nelson-Williams, Carol and Loring, Erin and Galm, Amy and Kahle, Kristopher T and Steinbacher, Derek M and Larysz, Dawid and Persing, John A and Lifton, Richard P} }