Key result
Whole-genome and RNA sequencing identified pathogenic compound heterozygous RYR1 intronic variants in a patient with severe congenital myopathy who remained undiagnosed after whole-exome sequencing.
Why the study?
Congenital myopathy presents a diagnostic challenge requiring multiple testing modalities, and the clinical superiority of whole-genome sequencing versus whole-exome sequencing remains an ongoing debate.
Case Report (n=1)
Clinical RNA sequencing following whole-genome sequencing can successfully identify and confirm the pathogenicity of intronic variants in patients with complex congenital phenotypes who remain undiagnosed after whole-exome sequencing.
May warrant WGS/RNA-seq in WES-negative congenital myopathy; leaves open validation of RYR1 intronic variants in larger cohorts.
BACKGROUND: Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1-related myopathies (RYR1-RM); the most common subgroup of congenital myopathies. METHODS: Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole-exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole-genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis. RESULTS: WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1-RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries. CONCLUSION: While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1-RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.
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Shillington et al. (2021) conducted a case report in Congenital myopathy (RYR1-RM) (n=1). Whole-genome sequencing and RNA sequencing vs. Whole-exome sequencing and standard genetic testing was evaluated on Identification of genetic etiology. Whole-genome and RNA sequencing identified pathogenic compound heterozygous RYR1 intronic variants in a patient with severe congenital myopathy who remained undiagnosed after whole-exome sequencing.
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