BDV-syndrome: An emerging syndrome with profound obesity and neurodevelopmental delay resembling Prader-Willi syndrome

2021 ◽  
Author(s):  
Elisabeth Bosch ◽  
Moritz Hebebrand ◽  
Bernt Popp ◽  
Theresa Penger ◽  
Bettina Behring ◽  
...  
Keyword(s):  
Clinical Features ◽  
Large Scale ◽  
Hypogonadotropic Hypogonadism ◽  
Computational Modelling ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Human Phenotype ◽  
Neurodevelopmental Delay ◽  
Missense Variants ◽  
Severely Obese

Abstract Context CPE encodes carboxypeptidase E, an enzyme which converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, four individuals from two families with core clinical features including morbid obesity, neurodevelopmental delay and hypogonadotropic hypogonadism, harbouring biallelic loss-of-function CPE variants, were reported. Objective We describe four affected individuals from three unrelated consanguineous families, two siblings of Syrian, one of Egyptian and one of Pakistani descent, all harbouring novel homozygous CPE loss-of-function variants. Methods After excluding Prader-Willi syndrome, exome sequencing was performed in both Syrian siblings. The variants identified in the other two individuals were reported as research variants in a large scale exome study and in ClinVar database. Computational modelling of all possible missense alterations allowed assessing CPE tolerance to missense variants. Results All affected individuals were severely obese with neurodevelopmental delay and other endocrine anomalies. Three individuals from two families shared the same CPE homozygous truncating variant c.361C>T, p.(Arg121*), while the fourth carried the c.994del, p.(Ser333Alafs*22) variant. Comparison of clinical features with previously described cases and standardization according to the Human Phenotype Ontology indicated a recognisable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes. Conclusions Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognisable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism and hypothyroidism. BDV syndrome resembles Prader-Willi syndrome. Our findings suggested that missense variants may also be clinically relevant.

scholarly journals Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability

2017 ◽  
Vol 55 (8) ◽  
pp. 561-566 ◽  
Author(s):  
Genay O Pilarowski ◽  
Hilary J Vernon ◽  
Carolyn D Applegate ◽  
Leandros Boukas ◽  
Megan T Cho ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Large Fraction ◽  
Chromatin Modification ◽  
Dominant Negative ◽  
Chromatin Remodeler ◽  
Cultured Fibroblasts ◽  
Human Phenotype ◽  
Missense Variants ◽  
Neurological Phenotype

BackgroundThe list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.ObjectivesTo explore whether variants in CHD1 are associated with a human phenotype.MethodsWe used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.ResultsHere we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.ConclusionsOur results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.

scholarly journals The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy

2018 ◽  
Author(s):  
Moritz Hebebrand ◽  
Ulrike Hüffmeier ◽  
Steffen Uebe ◽  
Arif B. Ekici ◽  
Cornelia Kraus ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Clinical Features ◽  
De Novo ◽  
Three Dimensional ◽  
Clinical Information ◽  
Amino Acid Position ◽  
Terminal Region ◽  
Autosomal Dominant Disorder ◽  
Human Phenotype ◽  
Missense Variants

ABSTRACTBackgroundThe TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.ResultsIn three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (70%), although reporting was incomplete in the different studies. We identified a total of 121 distinct variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein modelling, 38.6% of all disease causing variants including those in the C-terminal region are predicted to affect binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.ConclusionsWith 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.

scholarly journals Predicting functional effect of missense variants using graph attention neural networks

2021 ◽  
Author(s):  
Haicang Zhang ◽  
Michelle S. Xu ◽  
Wendy K. Chung ◽  
Yufeng Shen
Keyword(s):  
Neural Networks ◽  
Large Scale ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Missense Variants ◽  
Scale Population ◽  
Scan Data ◽  
Main Component

AbstractAccurate prediction of damaging missense variants is critically important for interpretating genome sequence. While many methods have been developed, their performance has been limited. Recent progress in machine learning and availability of large-scale population genomic sequencing data provide new opportunities to significantly improve computational predictions. Here we describe gMVP, a new method based on graph attention neural networks. Its main component is a graph with nodes capturing predictive features of amino acids and edges weighted by coevolution strength, which enables effective pooling of information from local protein sequence context and functionally correlated distal positions. Evaluated by deep mutational scan data, gMVP outperforms published methods in identifying damaging variants in TP53, PTEN, BRCA1, and MSH2. Additionally, it achieves the best separation of de novo missense variants in neurodevelopmental disorder cases from the ones in controls. Finally, the model supports transfer learning to optimize gain- and loss-of-function predictions in sodium and calcium channels. In summary, we demonstrate that gMVP can improve interpretation of missense variants in clinical testing and genetic studies.

scholarly journals Classifying disease-associated variants using measures of protein activity and stability

2019 ◽  
Author(s):  
Michael Maglegaard Jepsen ◽  
Douglas M. Fowler ◽  
Rasmus Hartmann-Petersen ◽  
Amelie Stein ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Protein Stability ◽  
Computational Methods ◽  
Genetic Disorders ◽  
Computational Modelling ◽  
Missense Variant ◽  
Loss Of Function ◽  
Protein Activity ◽  
Missense Variants ◽  
Tensin Homolog ◽  
Pathogenic Variants

AbstractDecreased cost of human exome and genome sequencing provides new opportunities for diagnosing genetic disorders, but we need better and more robust methods for interpreting sequencing results including determining whether and by which mechanism a specific missense variants may be pathogenic. Using the protein PTEN (phosphatase and tensin homolog) as an example, we show how recent developments in both experiments and computational modelling can be used to determine whether a missense variant is likely to be pathogenic. One approach relies on multiplexed experiments that enable determination of the effect of all possible individual missense variants in a cellular assay. Another approach is to use computational methods to predict variant effects. We compare two different multiplexed experiments and two computational methods to classify variant effects in PTEN. We distinguish between methods that focus on effects on protein stability and protein-specific methods that are more directly related to enzyme activity. Our results on PTEN suggest that ~60% of pathogenic variants cause loss of function because they destabilise the folded protein which is subsequently degraded. Methods that quantify a broader range of effects on PTEN activity perform better at predicting variant effects. Either experimental method performs better than the corresponding computational predictions, so that e.g. experiments that probe cellular abundance perform better at identifying pathogenic variants than predictions of thermodynamic stability. Our results suggest that loss of stability of PTEN is a key driver for disease, and we hypothesize that experiments and prediction methods that probe protein stability can be used to find variants with similar mechanisms in other genes.

scholarly journals Quantifying the unobserved protein-coding variants in human populations provides a roadmap for large-scale sequencing projects

2015 ◽  
Author(s):  
James Zou ◽  
Gregory Valiant ◽  
Paul Valiant ◽  
Konrad Karczewski ◽  
Siu On Chan ◽  
...  
Keyword(s):  
Frequency Distribution ◽  
Statistical Power ◽  
Large Scale ◽  
Rare Variants ◽  
Human Populations ◽  
Loss Of Function ◽  
Protein Coding ◽  
Missense Variants ◽  
Healthy Humans ◽  
Coding Variants

As new proposals aim to sequence ever larger collection of humans, it is critical to have a quantitative framework to evaluate the statistical power of these projects. We developed a new algorithm, UnseenEst, and applied it to the exomes of 60,706 individuals to estimate the frequency distribution of all protein-coding variants, including rare variants that have not been observed yet in the current cohorts. Our results quantified the number of new variants that we expect to identify as sequencing cohorts reach hundreds of thousands of individuals. With 500K individuals, we find that we expect to capture 7.5% of all possible loss-of-function variants and 12% of all possible missense variants. We also estimate that 2,900 genes have loss-of-function frequency of less than 0.00001 in healthy humans, consistent with very strong intolerance to gene inactivation.

scholarly journals Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability

2021 ◽  
Author(s):  
Natja Haag ◽  
Ene-Choo Tan ◽  
Matthias Begemann ◽  
Lars Buschmann ◽  
Florian Kraft ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Hedgehog Signaling ◽  
Heart Defects ◽  
Hypogonadotropic Hypogonadism ◽  
Loss Of Function ◽  
Reproductive Disorders ◽  
Developmental Defects ◽  
Human Phenotype ◽  
Repeat Domain ◽  
Independent Families

AbstractHeterozygous missense variants in the WD repeat domain 11 (WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11 in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11 knockdown. We here report biallelic loss-of-function variants in the WDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11 variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11 variants result in a clinically distinct entity.

scholarly journals Exome-by-phenome-wide rare variant gene burden association with electronic health record phenotypes

2019 ◽  
Author(s):  
Joseph Park ◽  
Nathan Katz ◽  
Xinyuan Zhang ◽  
Anastasia M Lucas ◽  
Anurag Verma ◽  
...  
Keyword(s):  
Large Scale ◽  
Stop Codon ◽  
Association Studies ◽  
Whole Genome Sequencing Data ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Missense Variants ◽  
Whole Exome ◽  
Wide Scale ◽  
Electronic Health

AbstractBackgroundBy coupling large-scale DNA sequencing with electronic health records (EHR), “genome-first” approaches can enhance our understanding of the contribution of rare genetic variants to disease. Aggregating rare, loss-of-function variants in a candidate gene into a “gene burden” to test for association with EHR phenotypes can identify both known and novel clinical implications for the gene in human disease. However, this methodology has not yet been applied on both an exome-wide and phenome-wide scale, and the clinical ontologies of rare loss-of-function variants in many genes have yet to be described.MethodsWe leveraged whole exome sequencing (WES) data in participants (N=11,451) in the Penn Medicine Biobank (PMBB) to address on an exome-wide scale the association of a burden of rare loss-of-function variants in each gene with diverse EHR phenotypes using a phenome-wide association study (PheWAS) approach. For discovery, we collapsed rare (minor allele frequency (MAF) ≤ 0.1%) predicted loss-of-function (pLOF) variants (i.e. frameshift insertions/deletions, gain/loss of stop codon, or splice site disruption) per gene to perform a gene burden PheWAS. Subsequent evaluation of the significant gene burden associations was done by collapsing rare (MAF ≤ 0.1%) missense variants with Rare Exonic Variant Ensemble Learner (REVEL) scores ≥ 0.5 into corresponding yet distinct gene burdens, as well as interrogation of individual low-frequency to common (MAF > 0.1%) pLOF variants and missense variants with REVEL≥ 0.5. We replicated our findings using the UK Biobank’s (UKBB) whole exome sequence dataset (N=49,960).ResultsFrom the pLOF-based discovery phase, we identified 106 gene burdens with phenotype associations at p<10-6 from our exome-by-phenome-wide association studies. Positive-control associations included TTN (cardiomyopathy, p=7.83E-13), MYBPC3 (hypertrophic cardiomyopathy, p=3.48E-15), CFTR (cystic fibrosis, p=1.05E-15), CYP2D6 (adverse effects due to opiates/narcotics, p=1.50E-09), and BRCA2 (breast cancer, p=1.36E-07). Of the 106 genes, 12 gene-phenotype relationships were also detected by REVEL-informed missense-based gene burdens and 19 by single-variant analyses, demonstrating the robustness of these gene-phenotype relationships. Three genes showed evidence of association using both additional methods (BRCA1, CFTR, TGM6), leading to a total of 28 robust gene-phenotype associations within PMBB. Furthermore, replication studies in UKBB validated 30 of 106 gene burden associations, of which 12 demonstrated robustness in PMBB.ConclusionOur study presents 12 exome-by-phenome-wide robust gene-phenotype associations, which include three proof-of-concept associations and nine novel findings. We show the value of aggregating rare pLOF variants into gene burdens on an exome-wide scale for unbiased association with EHR phenotypes to identify novel clinical ontologies of human genes. Furthermore, we show the significance of evaluating gene burden associations through complementary, yet non-overlapping genetic association studies from the same dataset. Our results suggest that this approach applied to even larger cohorts of individuals with WES or whole-genome sequencing data linked to EHR phenotype data will yield many new insights into the relationship of genetic variation and disease phenotypes.

scholarly journals Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders

2021 ◽  
Author(s):  
Katherine Crawford ◽  
Julie Xian ◽  
Katherine L. Helbig ◽  
Peter D. Galer ◽  
Shridhar Parthasarathy ◽  
...  
Keyword(s):  
Clinical Features ◽  
Phenotypic Variance ◽  
Loss Of Function ◽  
Phenotypic Data ◽  
Human Phenotype ◽  
Pathogenic Variants ◽  
Neonatal Onset ◽  
Behavioral Abnormalities ◽  
Wide Range ◽  
Phenotype Analysis

Abstract Purpose Pathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype–phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed. Methods We extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the NaV1.2 protein. Results We identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance. Conclusion Our work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype–phenotype correlations along a multidimensional spectrum.

Suppressors of a Cold-Sensitive Mutation in Yeast U4 RNA Define Five Domains in the Splicing Factor Prp8 That Influence Spliceosome Activation

Genetics ◽  
2000 ◽  
Vol 155 (4) ◽  
pp. 1667-1682 ◽  
Author(s):  
Andreas N Kuhn ◽  
David A Brow
Keyword(s):  
Large Scale ◽  
Splicing Factor ◽  
Cold Sensitivity ◽  
Splicing Factors ◽  
Loss Of Function ◽  
U1 Snrnp ◽  
Snrnp Protein ◽  
Cold Sensitive ◽  
Spliceosome Activation ◽  
U4 Rna

AbstractThe highly conserved splicing factor Prp8 has been implicated in multiple stages of the splicing reaction. However, assignment of a specific function to any part of the 280-kD U5 snRNP protein has been difficult, in part because Prp8 lacks recognizable functional or structural motifs. We have used a large-scale screen for Saccharomyces cerevisiae PRP8 alleles that suppress the cold sensitivity caused by U4-cs1, a mutant U4 RNA that blocks U4/U6 unwinding, to identify with high resolution five distinct regions of PRP8 involved in the control of spliceosome activation. Genetic interactions between two of these regions reveal a potential long-range intramolecular fold. Identification of a yeast two-hybrid interaction, together with previously reported results, implicates two other regions in direct and indirect contacts to the U1 snRNP. In contrast to the suppressor mutations in PRP8, loss-of-function mutations in the genes for two other splicing factors implicated in U4/U6 unwinding, Prp44 (Brr2/Rss1/Slt22/Snu246) and Prp24, show synthetic enhancement with U4-cs1. On the basis of these results we propose a model in which allosteric changes in Prp8 initiate spliceosome activation by (1) disrupting contacts between the U1 snRNP and the U4/U6-U5 tri-snRNP and (2) orchestrating the activities of Prp44 and Prp24.

scholarly journals Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

2021 ◽  
Author(s):  
Paolo Zanoni ◽  
Katharina Steindl ◽  
Deepanwita Sengupta ◽  
Pascal Joset ◽  
Angela Bahr ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Mild Phenotype ◽  
Psychological Issues ◽  
Missense Variants ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
In Silico Modeling ◽  
And Function ◽  
Methylation Activity

Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

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