Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype.
Priolo Manuela,Radio Francesca Clementina,Pizzi Simone,Pintomalli Letizia,Pantaleoni Francesca,Mancini Cecilia,Cordeddu Viviana,Africa Emilio,Mammì Corrado,Dallapiccola Bruno,Tartaglia Marco +10 more
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TLDR
In this paper, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition.Abstract:
Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.read more
References
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Posted ContentDOI
Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM
TL;DR: BWA-MEM automatically chooses between local and end-to-end alignments, supports paired-end reads and performs chimeric alignment, which is robust to sequencing errors and applicable to a wide range of sequence lengths from 70bp to a few megabases.
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A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3
Pablo Cingolani,Adrian E. Platts,Le Lily Wang,M. Coon,Tung T. Nguyen,Luan Wang,Susan Land,Xiangyi Lu,Douglas M. Ruden +8 more
TL;DR: It appears that the 5′ and 3′ UTRs are reservoirs for genetic variations that changes the termini of proteins during evolution of the Drosophila genus.
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From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline
Géraldine A. Van der Auwera,Mauricio O. Carneiro,Christopher Hartl,Ryan Poplin,Guillermo del Angel,Ami Levy-Moonshine,Tadeusz Jordan,Khalid Shakir,David Roazen,Joel Thibault,Eric Banks,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark A. DePristo +14 more
TL;DR: This unit describes how to use BWA and the Genome Analysis Toolkit to map genome sequencing data to a reference and produce high‐quality variant calls that can be used in downstream analyses.
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A general framework for estimating the relative pathogenicity of human genetic variants
Martin Kircher,Daniela Witten,Preti Jain,Brian J. O'Roak,Brian J. O'Roak,Gregory M. Cooper,Jay Shendure +6 more
TL;DR: The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method.
Journal ArticleDOI
The human splicing code reveals new insights into the genetic determinants of disease
Hui Yuan Xiong,Babak Alipanahi,Babak Alipanahi,Leo J. Lee,Leo J. Lee,Hannes Bretschneider,Daniele Merico,Ryan K. C. Yuen,Yimin Hua,Serge Gueroussov,Hamed S. Najafabadi,Hamed S. Najafabadi,Timothy P. Hughes,Quaid Morris,Yoseph Barash,Adrian R. Krainer,Nebojsa Jojic,Stephen W. Scherer,Benjamin J. Blencowe,Brendan J. Frey +19 more
TL;DR: A computational model is developed that scores how strongly genetic variants affect RNA splicing, a critical step in gene expression whose disruption contributes to many diseases, including cancers and neurological disorders, and provides insights into the role of aberrant splicing in disease.
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