Mutations in PIK3R1 Cause SHORT Syndrome
David A. Dyment,Amanda C. Smith,Diana Alcantara,Jeremy Schwartzentruber,Lina Basel-Vanagaite,Cynthia J. Curry,I. Karen Temple,I. Karen Temple,William Reardon,Sahar Mansour,Mushfequr R. Haq,Rodney D. Gilbert,Ordan J. Lehmann,Megan R. Vanstone,Chandree L. Beaulieu,Jacek Majewski,Dennis E. Bulman,Mark O'Driscoll,Kym M. Boycott,A. Micheil Innes,A. Micheil Innes +20 more
TLDR
The findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.Abstract:
SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs∗18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657∗]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.read more
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Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance
Luca A. Lotta,Pawan Gulati,Felix R. Day,Felicity Payne,Halit Ongen,Martijn van de Bunt,Martijn van de Bunt,Kyle J. Gaulton,John D. Eicher,Stephen J. Sharp,Jian'an Luan,Emanuella De Lucia Rolfe,Isobel D. Stewart,Eleanor Wheeler,Sara M. Willems,Claire Adams,Hanieh Yaghootkar,Nita G. Forouhi,Kay-Tee Khaw,Andrew D. Johnson,Robert K. Semple,Timothy M. Frayling,John R. B. Perry,Emmanouil T. Dermitzakis,Mark I. McCarthy,Mark I. McCarthy,Inês Barroso,Inês Barroso,Nicholas J. Wareham,David B. Savage,Claudia Langenberg,Stephen O'Rahilly,Robert A. Scott +32 more
TL;DR: The findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
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FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project
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TL;DR: The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers and discussed the way forward for rare-disease genetic discovery both in Canada and internationally.
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Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K
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References
More filters
Journal ArticleDOI
The Sequence Alignment/Map format and SAMtools
Heng Li,Bob Handsaker,Alec Wysoker,T. J. Fennell,Jue Ruan,Nils Homer,Gabor T. Marth,Gonçalo R. Abecasis,Richard Durbin +8 more
TL;DR: SAMtools as discussed by the authors implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments.
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
Journal ArticleDOI
Critical nodes in signalling pathways: Insights into insulin action
TL;DR: The concept of 'critical nodes' is used to define the important junctions in these pathways and illustrate their unique role using insulin signalling as a model system.
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