Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Mol Genet Genomic Med. 2021 Oct;9(10):e1804. doi: 10.1002/mgg3.1804. Epub 2021 Sep 16.
Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1-related myopathies (RYR1-RM); the most common subgroup of congenital myopathies.
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.
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.
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.
RYR1（OMIM#180901）基因的缺陷导致 Ryanodine 受体 1 相关肌病（RYR1-RM）；这是先天性肌病最常见的亚组。
先天性肌病由于需要多种检测方式来确定许多不同的遗传病因，因此具有诊断挑战性。在这种情况下，患者在进行全外显子组测序（WES）、染色体微阵列、甲基化分析、靶向缺失和重复研究以及靶向重复扩展研究后仍然未被诊断。然后，作为一项研究的一部分，进行临床全基因组测序（WGS）以确定诊断。
WGS 鉴定出 RYR1 内含子杂合变异体，RNA 测序证实这两种变异均具有致病性，导致 RYR1-RM 的表型为严重先天性低张力，出生时伴有呼吸衰竭、新生儿脑出血和先天性心脏病，涉及大动脉转位。
虽然对于疑似遗传疾病的患者，WGS 与 WES 的临床优越性存在争议，但这种情况突显了 WES 的弱点，以及 WGS 紧随 WES 或甚至在 WES 呈阴性后终止进一步遗传检测的情况下，诊断时间的成本和延迟。虽然对于许多内含子变异仍然存在知识空白，但转录组分析提供了一种验证这些变异引起的功能障碍的方法，从而允许进行适当的致病性分类。这是第二个报告 RYR1-RM 患者存在致病性内含子变异的病例，临床 RNA 检测证实了变异的致病性，因此该诊断表明对于某些患者，需要对患者的基因组和转录组进行仔细分析，以进行全面的基因评估。该患者的诊断之旅突出了早期、快速 WGS 的重要性。
