Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis.

Molecular Genetics & Genomic Medicine
Odelia ChorinGilad D Evrony

Abstract

Over half of children with rare genetic diseases remain undiagnosed despite maximal clinical evaluation and DNA-based genetic testing. As part of an Undiagnosed Diseases Program applying transcriptome (RNA) sequencing to identify the causes of these unsolved cases, we studied a child with severe infantile osteopetrosis leading to cranial nerve palsies, bone deformities, and bone marrow failure, for whom whole-genome sequencing was nondiagnostic. We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies. We identified a pathogenic deep intronic variant in CLCN7 creating an unexpected, frameshifting pseudoexon causing complete loss of function. Functional studies, including osteoclastogenesis and bone resorption assays, confirmed normal osteoclast differentiation but loss of osteoclast function. This is the first report of a pathogenic deep intronic variant in CLCN7, and our approach provides a model for systematic identification of noncoding variants causing osteopetrosis-a disease for which molecular-genetic diagnosis can be pivotal for potentially curative hematopoietic stem cell transplantation. Our work illustrates that cryptic splice var...Continue Reading

References

Oct 16, 2007·Bone·Andrea Del FattoreAnna Teti
Oct 30, 2008·Calcified Tissue International·Anita Vibsig Neutzsky-WulffKim Henriksen
Dec 17, 2008·Calcified Tissue International·Anna VillaCristina Sobacchi
Feb 24, 2009·Orphanet Journal of Rare Diseases·Zornitza Stark, Ravi Savarirayan
Jul 24, 2013·Nature Reviews. Endocrinology·Cristina SobacchiMiep H Helfrich
Nov 23, 2013·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Xueqiu JianXiaoming Liu
Feb 11, 2015·Advanced Drug Delivery Reviews·Richard S GearyC Frank Bennett
Apr 2, 2015·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Eleonora PalaganoCristina Sobacchi
Apr 16, 2015·International Journal of Endocrinology·Amélie E CoudertAndrea Del Fattore
May 9, 2015·Science·Marta MeléRoderic Guigó
Jul 15, 2015·Human Molecular Genetics·Feng Zhang, James R Lupski
Jul 15, 2015·American Journal of Human Genetics·Jessica X ChongMichael J Bamshad
Dec 4, 2015·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Kyle RettererSherri Bale
Apr 17, 2016·Nucleic Acids Research·Rudolph L Juliano
Jul 29, 2016·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Eleonora PalaganoCristina Sobacchi
Apr 21, 2017·Science Translational Medicine·Beryl B CummingsDaniel G MacArthur
May 6, 2017·American Journal of Human Genetics·Kym M BoycottHanns Lochmüller
May 13, 2017·Human Genetics·Rita Vaz-DragoMaria Carmo-Fonseca
Jun 29, 2017·The Journal of Clinical Endocrinology and Metabolism·Calvin C WuLynda E Polgreen
Jan 5, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Nick DragojlovicLarry D Lynd
Jan 18, 2018·Current Osteoporosis Reports·Eleonora PalaganoAnna Villa
Jan 27, 2018·Journal of Inherited Metabolic Disease·Laura S KremerHolger Prokisch
Aug 10, 2018·Experimental & Molecular Medicine·Brian S Gloss, Marcel E Dinger
Oct 12, 2018·The New England Journal of Medicine·Kimberly SplinterUNKNOWN Undiagnosed Diseases Network
Oct 30, 2018·Nucleic Acids Research·Philipp RentzschMartin Kircher
Jan 22, 2019·Cell·Kishore JaganathanKyle Kai-How Farh
Mar 5, 2019·American Journal of Human Genetics·Hernan D GonorazkyJames J Dowling
Mar 7, 2019·Frontiers in Endocrinology·Sara PennaAnna Villa
Oct 10, 2019·The New England Journal of Medicine·Jinkuk KimTimothy W Yu

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Methods Mentioned

BETA
X‐ray
biopsy

Software Mentioned

SpliceAI

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