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Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA sequencing
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Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA sequencing
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Journal Article
Diagnosing Cornelia de Lange syndrome and related neurodevelopmental disorders using RNA sequencing
2020
Overview
Purpose
Neurodevelopmental disorders represent a frequent indication for clinical exome sequencing. Fifty percent of cases, however, remain undiagnosed even upon exome reanalysis. Here we show RNA sequencing (RNA-seq) on human B-lymphoblastoid cell lines (LCL) is highly suitable for neurodevelopmental Mendelian gene testing and demonstrate the utility of this approach in suspected cases of Cornelia de Lange syndrome (CdLS).
Methods
Genotype–Tissue Expression project transcriptome data for LCL, blood, and brain were assessed for neurodevelopmental Mendelian gene expression. Detection of abnormal splicing and pathogenic variants in these genes was performed with a novel RNA-seq diagnostic pipeline and using a validation CdLS-LCL cohort (
n
= 10) and test cohort of patients who carry a clinical diagnosis of CdLS but negative genetic testing (
n
= 5).
Results
LCLs share isoform diversity of brain tissue for a large subset of neurodevelopmental genes and express 1.8-fold more of these genes compared with blood (LCL,
n
= 1706; whole blood,
n
= 917). This enables testing of more than 1000 genetic syndromes. The RNA-seq pipeline had 90% sensitivity for detecting pathogenic events and revealed novel diagnoses such as abnormal splice products in
NIPBL
and pathogenic coding variants in
BRD4
and
ANKRD11
.
Conclusion
The LCL transcriptome enables robust frontline and/or reflexive diagnostic testing for neurodevelopmental disorders.
Publisher
Nature Publishing Group US,Elsevier Limited
Subject
/ Cell Cycle Proteins - genetics
/ Datasets
/ De Lange Syndrome - diagnosis
/ De Lange Syndrome - genetics
/ Genetics
/ Genomes
/ Genomics
/ Humans
/ Neurodevelopmental disorders
/ Neurodevelopmental Disorders - diagnosis
/ Neurodevelopmental Disorders - genetics
/ Patients
/ Principal components analysis
/ Proteins
