z-logo
open-access-imgOpen Access
Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis
Author(s) -
Chorin Odelia,
Yachelevich Naomi,
Mohamed Khaled,
Moscatelli Ilana,
Pappas John,
Henriksen Kim,
Evrony Gilad D.
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1405
Subject(s) - osteopetrosis , biology , transcriptome , genetics , osteoclast , deep sequencing , computational biology , gene , genome , gene expression , immunology , in vitro
Background 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. Methods We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies. Results 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. Conclusion 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 variants may elude DNA‐only sequencing and supports broad first‐line use of transcriptome sequencing for children with undiagnosed diseases.

The content you want is available to Zendy users.

Already have an account? Click here to sign in.
Having issues? You can contact us here