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

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.

• Publication year

  2020

• Venue

  Molecular Genetics & Genomic Medicine

• Publication date

  2020-07-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/mgg3.1405PMID 32691986PMCID 7549584
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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

  2020cited by this paper
• Antisense oligonucleotides targeting Notch2 ameliorate the osteopenic phenotype in a mouse model of Hajdu-Cheney syndrome

  2020cited by this paper
• Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

  2019cited by this paper
• Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease

  2019influential reference
• One Disease, Many Genes: Implications for the Treatment of Osteopetroses

  2019cited by this paper
• Machine Learning Approaches for the Prioritization of Genomic Variants Impacting Pre-mRNA Splicing

  2019cited by this paper
• Predicting Splicing from Primary Sequence with Deep Learning.

  2019influential reference
• Genetics of Osteopetrosis

  2018cited by this paper
• “Transcriptomics”: molecular diagnosis of inborn errors of metabolism via RNA-sequencing

  2018cited by this paper
• The cost and diagnostic yield of exome sequencing for children with suspected genetic disorders: a benchmarking study

  2018cited by this paper
• Realizing the significance of noncoding functionality in clinical genomics

  2018cited by this paper
• Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

  2018cited by this paper
• CADD: predicting the deleteriousness of variants throughout the human genome

  2018cited by this paper
• Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group

  2017influential reference
• Deep intronic mutations and human disease

  2017cited by this paper
• International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases

  2017cited by this paper
• Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

  2017cited by this paper
• Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

  2017cited by this paper
• Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

  2016cited by this paper
• The delivery of therapeutic oligonucleotides

  2016cited by this paper
• Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C>T mutation in CLCN7

  2016cited by this paper
• Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis

  2015cited by this paper
• Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data

  2015cited by this paper
• Clinical application of whole-exome sequencing across clinical indications

  2015cited by this paper
• The human transcriptome across tissues and individuals

  2015cited by this paper
• Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides.

  2015cited by this paper
• Non-coding genetic variants in human disease.

  2015cited by this paper
• Osteopetrosis and Its Relevance for the Discovery of New Functions Associated with the Skeleton

  2015cited by this paper
• The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

  2015cited by this paper
• Guidelines for investigating causality of sequence variants in human disease

  2014cited by this paper
• Osteopetrosis: genetics, treatment and new insights into osteoclast function

  2013influential reference
• In silico tools for splicing defect prediction - A survey from the viewpoint of end-users

  2013cited by this paper
• Molecular and clinical heterogeneity in CLCN7‐dependent osteopetrosis: report of 20 novel mutations

  2010cited by this paper
• Osteopetrosis

  2009cited by this paper
• Characterization of the Bone Phenotype in ClC-7-Deficient Mice

  2008cited by this paper
• Infantile Malignant, Autosomal Recessive Osteopetrosis: The Rich and The Poor

  2008cited by this paper
• Genetics, pathogenesis and complications of osteopetrosis.

  2008cited by this paper
• Pre-mRNA splicing.

  1994cited by this paper

• Nanopore adaptive sampling accurately detects nucleotide variants and improves the characterization of large‐scale rearrangement for the diagnosis of cancer predisposition

  2025cites this paper
• Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing

  2022cites this paper
• Lessons learned: next-generation sequencing applied to undiagnosed genetic diseases

  2022cites this paper
• CLCN7, a gene shared by autosomal recessive and autosomal dominant osteopetrosis.

  2022cites this paper
• Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation

  2021cites this paper
• Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

  2021cites this paper
• Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis

  2020cites this paper
• Subtrochanteric Femoral Fracture in a Patient with Osteopetrosis: Treated with Internal Fixation and Complicated by Intraoperative Femoral Neck Fracture

  2020influential citation