scholarly journals De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Aristides Hadjinicolaou ◽  
Kathie J. Ngo ◽  
Daniel Y. Conway ◽  
John P. Provias ◽  
Steven K. Baker ◽  
...  
Keyword(s):  
Network Analysis ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Neurological Diseases ◽  
Patient Data ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Gene Variation ◽  
Transcriptional Signature ◽  
Pathogenic Variants

AbstractPathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.

scholarly journals Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

2020 ◽  
Vol 28 (12) ◽  
pp. 1763-1768
Author(s):  
Thomas Bourinaris ◽  
◽  
Damian Smedley ◽  
Valentina Cipriani ◽  
Isabella Sheikh ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
De Novo ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Spastic Paraplegia ◽  
Sequencing Data ◽  
Juvenile Form ◽  
Pathogenic Variants ◽  
Degenerative Disorders ◽  
Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

scholarly journals Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome

2021 ◽  
Author(s):  
Jet van der Spek ◽  
Joery den Hoed ◽  
Lot Snijders Blok ◽  
Alexander J. M. Dingemans ◽  
Dick Schijven ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Human Phenotype ◽  
Variable Expressivity ◽  
Pathogenic Variants ◽  
Reduced Penetrance ◽  
Coding Variants

Interpretation of next-generation sequencing data of individuals with an apparent sporadic neurodevelopmental disorder (NDD) often focusses on pathogenic variants in genes associated with NDD, assuming full clinical penetrance with limited variable expressivity. Consequently, inherited variants in genes associated with dominant disorders may be overlooked when the transmitting parent is clinically unaffected. While de novo variants explain a substantial proportion of cases with NDDs, a significant number remains undiagnosed possibly explained by coding variants associated with reduced penetrance and variable expressivity. We characterized twenty families with inherited heterozygous missense or protein-truncating variants (PTVs) in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome, characterized by intellectual disability, speech delay and recognizable facial features (SNIBCPS). Notably, the majority of the inherited CHD3 variants were maternally transmitted. Computational facial and human phenotype ontology-based comparisons demonstrated that the phenotypic features of probands with inherited CHD3 variants overlap with the phenotype previously associated with de novo variants in the gene, while carrier parents are mildly or not affected, suggesting variable expressivity. Additionally, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of related healthy carriers with a CHD3 PTV, suggested that compensation of expression from the wildtype allele is unlikely to be an underlying mechanism. Our results point to a significant role of inherited variation in SNIBCPS, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation towards understanding the broader contributions of such variation to the landscape of human disease.

scholarly journals Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy

2020 ◽  
Author(s):  
Anna Letko ◽  
Ben Strugnell ◽  
Irene M. Häfliger ◽  
Julia M. Paris ◽  
Katie Waine ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Neuroaxonal Dystrophy ◽  
Histopathological Analysis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Genome Region ◽  
Pathogenic Variants ◽  
Progressive Ataxia ◽  
Intron 2

Abstract Sporadic occurrences of neurodegenerative disorders including neuroaxonal dystrophy (NAD) have been previously reported in sheep. However, so far no causative genetic variant has been found for ovine NAD. The aim of this study was to characterize the phenotype and the genetic aetiology of an early-onset neurodegenerative disorder observed in several lambs of purebred Swaledale sheep, a native English breed. Affected lambs showed progressive ataxia and stiff gait and subsequent histopathological analysis revealed the widespread presence of axonal spheroid indicating neuronal degeneration. Thus, the observed clinical phenotype could be explained by a novel form of NAD. After SNP genotyping and subsequent linkage mapping within a paternal half-sib pedigree with a total of five NAD-affected lambs, we identified two loss-of-function variants by whole-genome sequencing in the ovine PLA2G6 gene situated in a NAD-linked genome region on chromosome 3. All cases were carriers of a compound heterozygous splice site variant in intron 2 and a nonsense variant in exon 8. Herein we present evidence for the occurrence of a familial novel form of recessively inherited NAD in sheep due to allelic heterogeneity at PLA2G6. This study reports two pathogenic variants in PLA2G6 causing a novel form of NAD in Swaledale sheep which enables selection against this fatal disorder.

scholarly journals A large deletion in the COL2A1 gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle

2020 ◽  
Vol 62 (1) ◽  
Author(s):  
Joana Gonçalves Pontes Jacinto ◽  
Irene Monika Häfliger ◽  
Anna Letko ◽  
Cord Drögemüller ◽  
Jørgen Steen Agerholm
Keyword(s):  
De Novo ◽  
Genetic Disorders ◽  
Polymerase Chain Reaction Analysis ◽  
Large Deletion ◽  
Whole Genome Sequence ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Pathogenic Variants ◽  
Base Pair Deletion

Abstract Background Congenital bovine chondrodysplasia, also known as bulldog calf syndrome, is characterized by disproportionate growth of bones resulting in a shortened and compressed body, mainly due to reduced length of the spine and the long bones of the limbs. In addition, severe facial dysmorphisms including palatoschisis and shortening of the viscerocranium are present. Abnormalities in the gene collagen type II alpha 1 chain (COL2A1) have been associated with some cases of the bulldog calf syndrome. Until now, six pathogenic single-nucleotide variants have been found in COL2A1. Here we present a novel variant in COL2A1 of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of the COL2A1-related bulldog calf syndrome in cattle. Case presentation The calf was aborted at gestation day 264 and showed generalized disproportionate dwarfism, with a shortened compressed body and limbs, and dysplasia of the viscerocranium; a phenotype resembling bulldog calf syndrome due to an abnormality in COL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons of COL2A1. Polymerase chain reaction analysis and Sanger sequencing confirmed the breakpoints of the deletion and its absence in the genomes of both parents. Conclusions The pathological and genetic findings were consistent with a case of “bulldog calf syndrome”. The identified variant causing the syndrome was the result of a de novo mutation event that either occurred post-zygotically in the developing embryo or was inherited because of low-level mosaicism in one of the parents. The identified loss-of-function variant is pathogenic due to COL2A1 haploinsufficiency and represents the first structural variant causing bulldog calf syndrome in cattle. Furthermore, this case report highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for genetic disorders in cattle.

scholarly journals Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot

2021 ◽  
Author(s):  
Miriam S. Reuter ◽  
Rajiv R. Chaturvedi ◽  
Rebekah K. Jobling ◽  
Giovanna Pellecchia ◽  
Omar Hamdan ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Tetralogy Of Fallot ◽  
Protein Interaction ◽  
Single Gene ◽  
Patient Specific ◽  
P Value ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Functional Protein ◽  
Pathogenic Variants

Background - Tetralogy of Fallot (TOF), the most common cyanotic heart defect in newborns, has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes, and could contribute to delineating pathomechanisms. Methods - Using a clinically-driven strategy, we re-analyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease (CHD). Results - We confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3; n=14) and NOTCH1 (n=10), and identified 1-3 variants in each of 21 other genes, including ATRX , DLL4 , EP300 , GATA6 , JAG1 , NF1 , PIK3CA , RAF1 , RASA1 , SMAD2 , and TBX1 . In addition, multiple loss-of-function variants provided support for three emerging CHD/TOF candidate genes: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 63 probands (7.8%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (p-value 3.3e-16), with VEGFR2 ( KDR ) and NOTCH1 representing central nodes. Variants associated with arrhythmias/sudden death and/or heart failure indicated factors that could influence long-term outcomes. Conclusions - The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for KDR (VEGFR2) as a CHD/TOF gene, and for vascular endothelial growth factor (VEGF) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

102 Exome Sequencing Identifies Novel Molecular Determinants of Human Congenital Hydrocephalus

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 220-220
Author(s):  
Charuta Gavankar Furey ◽  
Jungmin Choi ◽  
Daniel Duran ◽  
Andrew T Timberlake ◽  
Xue Zeng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Statistical Significance ◽  
The United States ◽  
Congenital Hydrocephalus ◽  
Common Disease ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Whole Exome

Abstract INTRODUCTION Congenital hydrocephalus (CH), with an estimated prevalence of 1 in 1000 births, is the most common disease treated by pediatric neurosurgeons, and exerts a tremendous burden on the United States health care budget, consuming over $2 billion annually. Paradoxically, CH treatments remain inadequate, crude, and primarily symptomatic, comprised largely of surgical shunts riddled with infectious and mechanical complications. Despite evidence that genetic factors play a major role in the pathogenesis of CH an estimated 40% of human CH has a genetic etiology our knowledge of specific CH-causing mutations and their pathogenic mechanisms remains primitive. Understanding critical genetic drivers underlying human CH holds promise for the development of targeted therapies. However, traditional genetic approaches have been limited in their ability to identify causative CH genes because kindreds are rare, small in size, or appear to have sporadic inheritance patterns. Next-generation sequencing, and specifically whole exome sequencing (WES), can overcome these barriers to gene discovery. METHODS We performed whole-exome sequencing on DNA isolated from 130 patient-parent trios (affected patient and unaffected parents) and an additional 57 probands for a total of 187 CH patients with non-L1CAM primary CH. Exome-sequencing data from these 447 individuals was then analyzed to identify rare, de novo and transmitted mutations contributing to CH, and candidate mutations were subsequently confirmed by Sanger sequencing. RESULTS >Exome sequencing identified multiple novel and recurrent de novo and transmitted loss-of function gene mutations enriched in neurodevelopmental and ciliogenesis pathways. Binomial and case-control analyses confirmed exome-wide statistical significance of candidate genes, and functional modeling in Xenopus established gene causality. CONCLUSION These findings reveal novel disease-causing mutations in human CH, thereby providing new opportunities for improved prognostic assessment and non-invasive therapies.

scholarly journals Analyses of rare and common alleles in parent-proband trios implicate rare missense variants in SLC6A1 in schizophrenia and confirm the involvement of loss of function intolerant and neurodevelopmental disorder genes

2019 ◽  
Author(s):  
Elliott Rees ◽  
Jun Han ◽  
Joanne Morgan ◽  
Noa Carrera ◽  
Valentina Escott-Price ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Common Variant ◽  
Published Data ◽  
Gamma Aminobutyric Acid ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Polygenic Risk ◽  
Full Dataset ◽  
Risk Alleles

AbstractSchizophrenia is a highly polygenic disorder with important contributions coming from both common and rare risk alleles, the latter including CNVs and rare coding variants (RCVs), sometimes occurring as de novo variants (DNVs). We performed DNV analysis in whole exome-sequencing data obtained from a new sample of 613 schizophrenia trios, and combined this with published data for a total of 3,444 trios. Loss-of-function (LoF) DNVs were significantly enriched among 3,488 LoF intolerant genes in our new trio data (rate ratio (RR) (95% CI) = 2.23 (1.31, 3.79); p = 2.2 × 10−3), supporting previous findings. In the full dataset, genes associated with neurodevelopmental disorders (NDD; n=160) were significantly enriched for LoF DNVs (RR (95% CI) = 3.32 (2.0, 5.21); p = 7.4 × 10−6). Within this set of NDD genes, SLC6A1, encoding a gamma-aminobutyric acid transporter, was associated with missense-damaging DNVs (p = 5.2 × 10−5). Using data from a subset of 1,122 trios for which we had genome-wide common variant data, schizophrenia polygenic risk was significantly over-transmitted to probands (p = 2.6 × 10−60), as was bipolar disorder common variant polygenic risk (p = 5.7 × 10−17). We defined carriers of candidate schizophrenia-related DNVs as those with LoF or deletion DNVs in LoF intolerant or NDD genes. These individuals had significantly less over-transmission of common risk alleles than non-carriers (p = 3.5 × 10−4), providing robust support for the hypothesis that this set of DNVs is enriched for those related to schizophrenia.

scholarly journals Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

2021 ◽  
Author(s):  
Waheed Awotoye ◽  
Peter A. Mossey ◽  
Jacqueline B. Hetmanski ◽  
Lord Jephthah Joojo Gowans ◽  
Mekonen A. Eshete ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Association Studies ◽  
Whole Genome ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

Abstract The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

scholarly journals Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

2020 ◽  
Author(s):  
Dong Li ◽  
Qin Wang ◽  
Naihua N. Gong ◽  
Alina Kurolap ◽  
Hagit Baris Feldman ◽  
...  
Keyword(s):  
De Novo ◽  
Brain Size ◽  
Wide Spectrum ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Wild Type ◽  
Chromatin Remodeler ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
Facial Dysmorphia

Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature, and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

scholarly journals A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1275
Author(s):  
Pleuntje J. van der Sluijs ◽  
Mariëlle Alders ◽  
Alexander J. M. Dingemans ◽  
Kareesma Parbhoo ◽  
Bregje W. van Bon ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Case Series ◽  
Sequence Variants ◽  
Loss Of Function ◽  
Mild Phenotype ◽  
Variable Expression ◽  
Pathogenic Variants ◽  
Genetics And Genomics ◽  
Translational Start

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.

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