scholarly journals Heterozygous lamin B1 and lamin B2 variants cause primary microcephaly and define a novel laminopathy

2020 ◽  
Author(s):  
David A. Parry ◽  
◽  
Carol-Anne Martin ◽  
Philip Greene ◽  
Joseph A. Marsh ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Structural Integrity ◽  
De Novo ◽  
Nuclear Lamina ◽  
Primary Microcephaly ◽  
Conserved Residues ◽  
Lamin B ◽  
Lamin B1 ◽  
Pathogenic Variants ◽  
Major Structural Component

Abstract Purpose Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined. Methods We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes. Results Starting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments. Conclusion We identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B–associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

scholarly journals MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 663
Author(s):  
Stijn van de Plassche ◽  
Arjan PM de Brouwer
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Expression Patterns ◽  
Mediator Complex ◽  
Gene Expression Patterns ◽  
Facial Dysmorphism ◽  
Regulation Of Transcription ◽  
Feeding Difficulties ◽  
Missense Variants ◽  
Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

scholarly journals InDelible: Detection and Evaluation of Clinically-relevant Structural Variation from Exome Sequencing

2020 ◽  
Author(s):  
Eugene J. Gardner ◽  
Alejandro Sifrim ◽  
Sarah J. Lindsay ◽  
Elena Prigmore ◽  
Diana Rajan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Disorders ◽  
Structural Variation ◽  
Developmental Disorder ◽  
De Novo ◽  
Size Range ◽  
Diagnostic Yield ◽  
Structural Variations ◽  
Pathogenic Variants ◽  
Split Read

AbstractPurposeIdentifying structural variations (SVs) associated with developmental disorder (DD) patient phenotype missed by conventional approaches.MethodsWe have developed a novel SV discovery approach that mines split-read information, ‘InDelible’, and applied it to exome sequencing (ES) of 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study.ResultsUsing InDelible we were able to find 59 previously undetected variants in genes previously associated with DD, of which 49.2% (29) had phenotypic features that accord with those of the patient in which they were found, and were deemed plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.0% (n = 29 variants). Of particular interest were seven confirmed de novo SVs in the gene MECP2; these variants represent 31.8% of all de novo protein truncating variants in MECP2 among DDD patients.ConclusionInDelible provides a rapid framework for the discovery of likely pathogenic SVs that are likely to be missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES.

scholarly journals Pathogenicity and selective constraint on variation near splice sites

2018 ◽  
Author(s):  
Jenny Lord ◽  
Giuseppe Gallone ◽  
Patrick J. Short ◽  
Jeremy F. McRae ◽  
Holly Ironfield ◽  
...  
Keyword(s):  
Splice Site ◽  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Splice Sites ◽  
Sequencing Data ◽  
Pathogenic Variants ◽  
Unbiased Manner ◽  
Functional Relevance

AbstractMutations which perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7,833 probands with developmental disorders (DD) and their unaffected parents, as well as >60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice site, and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking non-canonical positions (27%), and calculated the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at non-canonical positions in splice sites. We estimate 35-40% of pathogenic variants in non-canonical splice site positions are missing from public databases.

scholarly journals De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Beryl Royer-Bertrand ◽  
Marine Jequier Gygax ◽  
Katarina Cisarova ◽  
Jill A. Rosenfeld ◽  
Jennifer A. Bassetti ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Calcium Channel ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Small Sample ◽  
Control Population ◽  
Pathogenic Variants ◽  
Developmental Regression ◽  
Short Period

Abstract Background De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Methods Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. Results We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. Limitations The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Conclusions Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

scholarly journals A map of constrained coding regions in the human genome

2017 ◽  
Author(s):  
James M. Havrilla ◽  
Brent S. Pedersen ◽  
Ryan M. Layer ◽  
Aaron R. Quinlan
Keyword(s):  
Human Genome ◽  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Protein Domain ◽  
De Novo Mutations ◽  
Protein Coding ◽  
Constrained Coding ◽  
Coding Regions ◽  
Pathogenic Variants

ABSTRACTDeep catalogs of genetic variation collected from many thousands of humans enable the detection of intraspecies constraint by revealing coding regions with a scarcity of variation. While existing techniques summarize constraint for entire genes, single metrics cannot capture the fine-scale variability in constraint within each protein-coding gene. To provide greater resolution, we have created a detailed map of constrained coding regions (CCRs) in the human genome by leveraging coding variation observed among 123,136 humans from the Genome Aggregation Database (gnomAD). The most constrained coding regions in our map are enriched for both pathogenic variants in ClinVar and de novo mutations underlying developmental disorders. CCRs also reveal protein domain families under high constraint, suggest unannotated or incomplete protein domains, and facilitate the prioritization of previously unseen variation in studies of disease. Finally, a subset of CCRs with the highest constraint likely exist within genes that cause yet unobserved human phenotypes owing to strong purifying selection.

scholarly journals Identification of lamin B–regulated chromatin regions based on chromatin landscapes

2015 ◽  
Vol 26 (14) ◽  
pp. 2685-2697 ◽  
Author(s):  
Xiaobin Zheng ◽  
Youngjo Kim ◽  
Yixian Zheng
Keyword(s):  
Embryonic Stem ◽  
Nuclear Lamina ◽  
Chromatin Interaction ◽  
Dependent Manner ◽  
Structural Components ◽  
Genomic Features ◽  
Lamin B ◽  
Lamin B1 ◽  
Repressive Chromatin

Lamins, the major structural components of the nuclear lamina (NL) found beneath the nuclear envelope, are known to interact with most of the nuclear peripheral chromatin in metazoan cells. Although NL–chromatin associations correlate with a repressive chromatin state, the role of lamins in tethering chromatin to NL and how such tether influences gene expression have remained challenging to decipher. Studies suggest that NL proteins regulate chromatin in a context-dependent manner. Therefore understanding the context of chromatin states based on genomic features, including chromatin–NL interactions, is important to the study of lamins and other NL proteins. By modeling genome organization based on combinatorial patterns of chromatin association with lamin B1, core histone modification, and core and linker histone occupancy, we report six distinct large chromatin landscapes, referred to as histone lamin landscapes (HiLands)-red (R), -orange (O), -yellow (Y), -green (G), -blue (B), and -purple (P), in mouse embryonic stem cells (mESCs). This HiLands model demarcates the previously mapped lamin-associated chromatin domains (LADs) into two HiLands, HiLands-B and HiLands-P, which are similar to facultative and constitutive heterochromatins, respectively. Deletion of B-type lamins in mESCs caused a reduced interaction between regions of HiLands-B and NL as measured by emerin–chromatin interaction. Our findings reveal the importance of analyzing specific chromatin types when studying the function of NL proteins in chromatin tether and regulation.

scholarly journals Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1116
Author(s):  
Ester Di Muro ◽  
Pietro Palumbo ◽  
Mario Benvenuto ◽  
Maria Accadia ◽  
Marilena Carmela Di Giacomo ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Sequencing Analysis ◽  
Cohesin Complex ◽  
Mild Intellectual Disability ◽  
Pathogenic Variants ◽  
Core Proteins ◽  
Next Generation Sequencing Analysis ◽  
Cornelia De Lange

The cohesin complex is a large evolutionary conserved functional unit which plays an essential role in DNA repair and replication, chromosome segregation and gene expression. It consists of four core proteins, SMC1A, SMC3, RAD21, and STAG1/2, and by proteins regulating the interaction between the complex and the chromosomes. Mutations in the genes coding for these proteins have been demonstrated to cause multisystem developmental disorders known as “cohesinopathies”. The most frequent and well recognized among these distinctive clinical conditions are the Cornelia de Lange syndrome (CdLS, OMIM 122470) and Roberts syndrome (OMIM 268300). STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. Pathogenic variants in STAG1 gene have recently been reported to cause an emerging syndromic form of neurodevelopmental disorder that is to date poorly characterized. Here, we describe a 5 year old female patient with neurodevelopmental delay, mild intellectual disability, dysmorphic features and congenital anomalies, in which next generation sequencing analysis allowed us to identify a novel pathogenic variation c.2769_2770del p.(Ile924Serfs*8) in STAG1 gene, which result to be de novo. The variant has never been reported before in medical literature and is absent in public databases. Thus, it is useful to expand the molecular spectrum of clinically relevant alterations of STAG1 and their phenotypic consequences.

Lamin B receptor: role on chromatin structure, cellular senescence and possibly aging

2020 ◽  
Vol 477 (14) ◽  
pp. 2715-2720
Author(s):  
Susana Castro-Obregón
Keyword(s):  
Cellular Senescence ◽  
Nuclear Membrane ◽  
Chromatin Structure ◽  
Cholesterol Synthesis ◽  
Reductase Activity ◽  
Chimeric Protein ◽  
Nuclear Lamina ◽  
Lamin B ◽  
Inner Nuclear Membrane ◽  
Lamin B Receptor

The nuclear envelope is composed by an outer nuclear membrane and an inner nuclear membrane, which is underlain by the nuclear lamina that provides the nucleus with mechanical strength for maintaining structure and regulates chromatin organization for modulating gene expression and silencing. A layer of heterochromatin is beneath the nuclear lamina, attached by inner nuclear membrane integral proteins such as Lamin B receptor (LBR). LBR is a chimeric protein, having also a sterol reductase activity with which it contributes to cholesterol synthesis. Lukasova et al. showed that when DNA is damaged by ɣ-radiation in cancer cells, LBR is lost causing chromatin structure changes and promoting cellular senescence. Cellular senescence is characterized by terminal cell cycle arrest and the expression and secretion of various growth factors, cytokines, metalloproteinases, etc., collectively known as senescence-associated secretory phenotype (SASP) that cause chronic inflammation and tumor progression when they persist in the tissue. Therefore, it is fundamental to understand the molecular basis for senescence establishment, maintenance and the regulation of SASP. The work of Lukasova et al. contributed to our understanding of cellular senescence establishment and provided the basis that lead to the further discovery that chromatin changes caused by LBR reduction induce an up-regulated expression of SASP factors. LBR dysfunction has relevance in several diseases and possibly in physiological aging. The potential bifunctional role of LBR on cellular senescence establishment, namely its role in chromatin structure together with its enzymatic activity contributing to cholesterol synthesis, provide a new target to develop potential anti-aging therapies.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals nanotatoR: a tool for enhanced annotation of genomic structural variants

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Surajit Bhattacharya ◽  
Hayk Barseghyan ◽  
Emmanuèle C. Délot ◽  
Eric Vilain
Keyword(s):  
De Novo ◽  
Genome Mapping ◽  
Gene List ◽  
Sufficient Information ◽  
Rna Seq ◽  
Structural Variants ◽  
De Novo Genome Assembly ◽  
Pathogenic Variants ◽  
Increased Sensitivity

Abstract Background Whole genome sequencing is effective at identification of small variants, but because it is based on short reads, assessment of structural variants (SVs) is limited. The advent of Optical Genome Mapping (OGM), which utilizes long fluorescently labeled DNA molecules for de novo genome assembly and SV calling, has allowed for increased sensitivity and specificity in SV detection. However, compared to small variant annotation tools, OGM-based SV annotation software has seen little development, and currently available SV annotation tools do not provide sufficient information for determination of variant pathogenicity. Results We developed an R-based package, nanotatoR, which provides comprehensive annotation as a tool for SV classification. nanotatoR uses both external (DGV; DECIPHER; Bionano Genomics BNDB) and internal (user-defined) databases to estimate SV frequency. Human genome reference GRCh37/38-based BED files are used to annotate SVs with overlapping, upstream, and downstream genes. Overlap percentages and distances for nearest genes are calculated and can be used for filtration. A primary gene list is extracted from public databases based on the patient’s phenotype and used to filter genes overlapping SVs, providing the analyst with an easy way to prioritize variants. If available, expression of overlapping or nearby genes of interest is extracted (e.g. from an RNA-Seq dataset, allowing the user to assess the effects of SVs on the transcriptome). Most quality-control filtration parameters are customizable by the user. The output is given in an Excel file format, subdivided into multiple sheets based on SV type and inheritance pattern (INDELs, inversions, translocations, de novo, etc.). nanotatoR passed all quality and run time criteria of Bioconductor, where it was accepted in the April 2019 release. We evaluated nanotatoR’s annotation capabilities using publicly available reference datasets: the singleton sample NA12878, mapped with two types of enzyme labeling, and the NA24143 trio. nanotatoR was also able to accurately filter the known pathogenic variants in a cohort of patients with Duchenne Muscular Dystrophy for which we had previously demonstrated the diagnostic ability of OGM. Conclusions The extensive annotation enables users to rapidly identify potential pathogenic SVs, a critical step toward use of OGM in the clinical setting.

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