scholarly journals Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Andrew T Timberlake ◽  
Jungmin Choi ◽  
Samir Zaidi ◽  
Qiongshi Lu ◽  
Carol Nelson-Williams ◽  
...  
Keyword(s):  
Epistatic Interaction ◽  
Osteoblast Differentiation ◽  
Genetic Basis ◽  
De Novo ◽  
Genetic Interaction ◽  
Cranial Sutures ◽  
Incomplete Penetrance ◽  
Common Variants ◽  
Neurologic Outcomes ◽  
Metopic Craniosynostosis

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.

scholarly journals Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

2021 ◽  
Vol 12 ◽  
Author(s):  
Martina Servetti ◽  
Livia Pisciotta ◽  
Elisa Tassano ◽  
Maria Cerminara ◽  
Lino Nobili ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Genetic Basis ◽  
De Novo ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Brain Diseases ◽  
Comparative Genomic ◽  
Incomplete Penetrance ◽  
Genetic Components ◽  
Complex Phenotypes

Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients’ phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients’ phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.

scholarly journals Genome sequences reveal global dispersal routes and suggest convergent genetic adaptations in seahorse evolution

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chunyan Li ◽  
Melisa Olave ◽  
Yali Hou ◽  
Geng Qin ◽  
Ralf F. Schneider ◽  
...  
Keyword(s):  
Coastal Waters ◽  
Genetic Basis ◽  
De Novo ◽  
Ocean Currents ◽  
Rapid Adaptation ◽  
Developmental Gene ◽  
De Novo Genome Assembly ◽  
Biogeographic Patterns ◽  
Hippocampus Erectus ◽  
New Habitats

AbstractSeahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats.

scholarly journals A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

2019 ◽  
Vol 28 (15) ◽  
pp. 2501-2513 ◽  
Author(s):  
Jacqueline A C Goos ◽  
Walter K Vogel ◽  
Hana Mlcochova ◽  
Christopher J Millard ◽  
Elahe Esfandiari ◽  
...  
Keyword(s):  
De Novo ◽  
Cranial Sutures ◽  
Coronal Suture ◽  
Nurd Complex ◽  
Binding Studies ◽  
Amino Terminal ◽  
Skull Vault ◽  
Order Of Magnitude ◽  
Transcriptional Complexes ◽  
Dynamics Simulations

Abstract Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4–MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.

scholarly journals Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1073
Author(s):  
Federica Tiberio ◽  
Ornella Parolini ◽  
Wanda Lattanzi
Keyword(s):  
Primary Cilium ◽  
Genetic Basis ◽  
Mendelian Inheritance ◽  
Craniofacial Development ◽  
Cranial Sutures ◽  
Craniofacial Malformation ◽  
Computational Annotation ◽  
Neural Crest Origin ◽  
Disease Associated Genes ◽  
Molecular Signals

Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

scholarly journals Mosaicism and incomplete penetrance of PCDH19 mutations

2018 ◽  
Vol 56 (2) ◽  
pp. 81-88 ◽  
Author(s):  
Aijie Liu ◽  
Xiaoxu Yang ◽  
Xiaoling Yang ◽  
Qixi Wu ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Male Patient ◽  
Sanger Sequencing ◽  
De Novo ◽  
Digital Pcr ◽  
The Other ◽  
Incomplete Penetrance ◽  
Female Patients ◽  
Targeted Next Generation Sequencing ◽  
Male Patients ◽  
Patients With Epilepsy

BackgroundMutations in the PCDH19 gene have mainly been reported in female patients with epilepsy. To date, PCDH19 mutations have been reported in hundreds of females and only in 10 mosaic male epileptic patients with mosaicism.ObjectiveWe aimed to investigate the occurrence of mosaic PCDH19 mutations in 42 families comprising at least one patient with PCDH19-related epilepsy.MethodsTwo male patients with mosaic PCDH19 variants were identified using targeted next-generation sequencing. Forty female patients with PCDH19 variants were identified by Sanger sequencing and Multiple Ligation Probe Amplification (MLPA). Microdroplet digital PCR was used to quantify the mutant allelic fractions (MAFs) in 20 families with PCDH19 variants.ResultsFive mosaic individuals, four males and one female, were identified in total. Mosaic variant was confirmed in multiple somatic tissues from one male patient and in blood from the other male patient. Among 22 female patients harbouring a newly occurred PCDH19 variant identified by Sanger sequencing and MLPA, Sanger sequencing revealed two mosaic fathers (9%, 2/22), one with two affected daughters and the other with an affected child. Two asymptomatic mosaic fathers were confirmed as gonosomal mosaicism, with MAFs ranging from 4.16% to 37.38% and from 1.27% to 19.13%, respectively. In 11 families with apparent de novo variants, 1 female patient was identified as a mosaic with a blood MAF of 26.72%.ConclusionOur study provides new insights into phenotype-genotype correlations in PCDH19 related epilepsy and the finding of high-frequency mosaicism has important implications for genetic counselling.

scholarly journals Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Courtney M. Karner ◽  
Seung-Yon Lee ◽  
Fanxin Long
Keyword(s):  
Protein Synthesis ◽  
Intracellular Signaling ◽  
Osteoblast Differentiation ◽  
De Novo ◽  
Bmp Signaling ◽  
Endoplasmic Reticulum Stress Response ◽  
Versus Protein ◽  
Mtorc1 Signaling ◽  
General Protein Synthesis ◽  
General Protein

ABSTRACT The bone morphogenetic protein (Bmp) family of secreted molecules has been extensively studied in the context of osteoblast differentiation. However, the intracellular signaling cascades that mediate the osteoblastogenic function of Bmp have not been fully elucidated. By profiling mRNA expression in the bone marrow mesenchymal progenitor cell line ST2, we discover that BMP2 induces not only genes commonly associated with ossification and mineralization but also genes important for general protein synthesis. We define the two groups of genes as mineralization related versus protein anabolism signatures of osteoblasts. Although it induces the expression of several Wnt genes, BMP2 activates the osteogenic program largely independently of de novo Wnt secretion. Remarkably, although Smad4 is necessary for the activation of the mineralization-related genes, it is dispensable for BMP2 to induce the protein anabolism signature, which instead critically depends on the transcription factor Atf4. Upstream of Atf4, BMP2 activates mTORC1 to stimulate protein synthesis, resulting in an endoplasmic reticulum stress response mediated by Perk. Thus, Bmp signaling induces osteoblast differentiation through both Smad4- and mTORC1-dependent mechanisms.

Abstract 367: Extreme High-Density Lipoprotein Cholesterol Genetics: An Assortment of Large and Small Polygenic Effects

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jacqueline S Dron ◽  
Jian Wang ◽  
Cécile Low-Kam ◽  
Sumeet A Khetarpal ◽  
John F Robinson ◽  
...  
Keyword(s):  
Large Scale ◽  
Genetic Basis ◽  
Rare Variants ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Copy Number Variations ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Targeted Next Generation Sequencing ◽  
Common Genetic Variants

Rationale: Although HDL-C levels are known to have a complex genetic basis, most studies have focused solely on identifying rare variants with large phenotypic effects to explain extreme HDL-C phenotypes. Objective: Here we concurrently evaluate the contribution of both rare and common genetic variants, as well as large-scale copy number variations (CNVs), towards extreme HDL-C concentrations. Methods: In clinically ascertained patients with low ( N =136) and high ( N =119) HDL-C profiles, we applied our targeted next-generation sequencing panel (LipidSeq TM ) to sequence genes involved in HDL metabolism, which were subsequently screened for rare variants and CNVs. We also developed a novel polygenic trait score (PTS) to assess patients’ genetic accumulations of common variants that have been shown by genome-wide association studies to associate primarily with HDL-C levels. Two additional cohorts of patients with extremely low and high HDL-C (total N =1,746 and N =1,139, respectively) were used for PTS validation. Results: In the discovery cohort, 32.4% of low HDL-C patients carried rare variants or CNVs in primary ( ABCA1 , APOA1 , LCAT ) and secondary ( LPL , LMF1 , GPD1 , APOE ) HDL-C–altering genes. Additionally, 13.4% of high HDL-C patients carried rare variants or CNVs in primary ( SCARB1 , CETP , LIPC , LIPG ) and secondary ( APOC3 , ANGPTL4 ) HDL-C–altering genes. For polygenic effects, patients with abnormal HDL-C profiles but without rare variants or CNVs were ~2-fold more likely to have an extreme PTS compared to normolipidemic individuals, indicating an increased frequency of common HDL-C–associated variants in these patients. Similar results in the two validation cohorts demonstrate that this novel PTS successfully quantifies common variant accumulation, further characterizing the polygenic basis for extreme HDL-C phenotypes. Conclusions: Patients with extreme HDL-C levels have various combinations of rare variants, common variants, or CNVs driving their phenotypes. Fully characterizing the genetic basis of HDL-C levels must extend to encompass multiple types of genetic determinants—not just rare variants—to further our understanding of this complex, controversial quantitative trait.

scholarly journals Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ute I Scholl ◽  
Gabriel Stölting ◽  
Carol Nelson-Williams ◽  
Alfred A Vichot ◽  
Murim Choi ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Early Onset ◽  
De Novo ◽  
Incomplete Penetrance ◽  
De Novo Mutations ◽  
Channel Inactivation ◽  
Aldosterone Production ◽  
Genome Level ◽  
Insight Into

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

Bicoronal and metopic craniosynostosis in association with a de novo unbalanced t(2;7) chromosomal translocation

2016 ◽  
Vol 173 (1) ◽  
pp. 274-279
Author(s):  
James J. O'Byrne ◽  
Helen Ryan ◽  
Dylan J. Murray ◽  
Regina Regan ◽  
David R. Betts ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Translocation ◽  
Metopic Craniosynostosis

scholarly journals Echolocation call frequency variation in horseshoe bats: molecular basis revealed by comparative transcriptomics

2020 ◽  
Vol 287 (1934) ◽  
pp. 20200875
Author(s):  
Haijian Sun ◽  
Wenli Chen ◽  
Jiaying Wang ◽  
Libiao Zhang ◽  
Stephen J. Rossiter ◽  
...  
Keyword(s):  
Genetic Basis ◽  
De Novo ◽  
Expression Profiles ◽  
Frequency Variation ◽  
Echolocation Call ◽  
Reverse Transcription Pcr ◽  
Strong Candidate ◽  
Horseshoe Bat ◽  
Candidate Loci ◽  
Horseshoe Bats

Recently diverged taxa with contrasting phenotypes offer opportunities for unravelling the genetic basis of phenotypic variation in nature. Horseshoe bats are a speciose group that exhibit a derived form of high-duty cycle echolocation in which the inner ear is finely tuned to echoes of the narrowband call frequency. Here, by focusing on three recently diverged subspecies of the intermediate horseshoe bat ( Rhinolophus affinis ) that display divergent echolocation call frequencies, we aim to identify candidate loci putatively involved in hearing frequency variation. We used de novo transcriptome sequencing of two mainland taxa ( himalayanus and macrurus ) and one island taxon ( hainanus ) to compare expression profiles of thousands of genes. By comparing taxa with divergent call frequencies (around 15 kHz difference), we identified 252 differentially expressed genes, of which six have been shown to be involved in hearing or deafness in human/mouse. To obtain further validation of these results, we applied quantitative reverse transcription–PCR to the candidate gene FBXL15 and found a broad association between the level of expression and call frequency across taxa. The genes identified here represent strong candidate loci associated with hearing frequency variation in bats.

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