Uncovering the genetic lesions underlying the most severe form of Hirschsprung disease by whole-genome sequencing

European Journal of Human Genetics : EJHG
Clara Sze-Man TangMaria-Mercè Garcia-Barceló

Abstract

Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells along a variable length of the distal intestine. A large proportion of HSCR patients remain genetically unexplained. We applied whole-genome sequencing (WGS) on 9 trios where the probands are sporadically affected with the most severe form of the disorder and harbor no coding sequence variants affecting the function of known HSCR genes. We found de novo protein-altering variants in three intolerant to change genes-CCT2, VASH1, and CYP26A1-for which a plausible link with the enteric nervous system (ENS) exists. De novo single-nucleotide and indel variants were present in introns and non-coding neighboring regions of ENS-related genes, including NRG1 and ERBB4. Joint analysis with those inherited rare variants found under recessive and/or digenic models revealed both patient-unique and shared genetic features where rare variants were found to be enriched in the extracellular matrix-receptor (ECM-receptor) pathway (p = 3.4 × 10-11). Delineation of the genetic profile of each patient might help finding common grounds that could lead to the discovery of shared molecules that could be used as drug targets for the currently ongoing cell t...Continue Reading

References

Feb 24, 2001·Journal of Medical Genetics·D WieczorekG Gillessen-Kaesbach
Apr 15, 2005·Nature·Eileen Sproat EmisonAravinda Chakravarti
Aug 21, 2007·Genes & Development·Gromoslaw A SmolenDaniel A Haber
Oct 26, 2007·Orphanet Journal of Rare Diseases·Livia Garavelli, Paola Cerruti Mainardi
Oct 30, 2007·Journal of Medical Genetics·J AmielUNKNOWN Hirschsprung Disease Consortium
Feb 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Maria-Mercè Garcia-BarceloPaul Kwong-Hang Tam
May 20, 2009·Bioinformatics·Heng Li, Richard Durbin
Jul 6, 2010·American Journal of Human Genetics·Eileen Sproat EmisonAravinda Chakravarti
Jul 10, 2010·Orphanet Journal of Rare Diseases·Francesco BrancatiEnza Maria Valente
Jan 7, 2011·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Aoife M Waters, Philip L Beales
Feb 1, 2012·Developmental Biology·Valentina SasselliAlan J Burns
May 17, 2012·PLoS Genetics·Clara Sze-Man TangMaria-Mercè Garcia-Barceló
Aug 28, 2012·Neuron·Genevieve KonopkaDaniel H Geschwind
Nov 1, 2013·Nucleic Acids Research·Jeffrey R MacDonaldStephen W Scherer
Feb 25, 2014·Communicative & Integrative Biology·Lei Shi
Jun 5, 2014·Nature·Christian GilissenJoris A Veltman
Jun 28, 2014·Genome Biology·Ryan M LayerIra M Hall
Aug 5, 2014·Nature Genetics·Kaitlin E SamochaMark J Daly
Sep 10, 2014·Current Protocols in Bioinformatics·Aaron R Quinlan
Sep 18, 2015·Nature Protocols·Hui Yang, Kai Wang
Nov 17, 2015·The Journal of Clinical Investigation·Rodolphe SoretUNKNOWN Ente-Hirsch Study Group
Nov 30, 2016·Genome Biology·Rocio Acuna-HidalgoAlexander Hoischen
Dec 8, 2016·Nucleic Acids Research·Damian SzklarczykChristian von Mering
Jan 15, 2017·Seminars in Cell & Developmental Biology·Nandor Nagy, Allan M Goldstein
Mar 3, 2017·Nature Genetics·Ashley P L MarshChristel Depienne
Mar 3, 2017·Nature Genetics·Saumya S JamuarTimothy W Yu

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Citations

Jul 30, 2019·Clinical Genetics·Berta Luzón-ToroSalud Borrego
Oct 17, 2018·Pediatric Investigation·Juntao KeXiaoping Miao
Feb 13, 2021·NAR Genomics and Bioinformatics·Xuehan ZhuangPak Chung Sham
Jan 25, 2020·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Ioan Ovidiu SirbuAlexander Radu Moise
Jan 27, 2021·The Journal of Clinical Investigation·Thuy-Linh LeNadège Bondurand
Aug 24, 2021·Frontiers in Pediatrics·Anwarul KarimPaul Kwong-Hang Tam

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Methods Mentioned

BETA
electrophoresis
Exome Sequencing
PLAT

Software Mentioned

DeNovoGear
LUMPY
DELLY
GATK
KGGSeq
CADD
Seeksv
GATK PhaseByTransmission
STRING
BEDTools

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Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.

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