PDF(Pubmed)
Abstract：
Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother\'s current pregnancy.
摘要：
DYNC2H1的双等位基因致病变异体是伴有或不伴有多指的短肋骨胸部发育不良III型的原因(OMIM#613091),一种以短肋骨引起的胸部发育不全为特征的骨骼纤毛病。在这份报告中,我们回顾了一名患者的病例，该患者在经历了继发于小范围的呼吸窘迫后，被送往印第安纳大学健康（IUH）的新生儿重症监护病房（NICU）接受呼吸支持，胸部狭窄导致限制性肺病。其他表型特征包括后轴多指，短的近端长骨，并注意到模棱两可的生殖器。外显子组测序（ES）揭示了DYNC2H1基因中的母系遗传的可能致病变体c.10322C>Tp。（Leu3448Pro）。然而,在父系等位基因上没有发现变异。检测DYNC2H1中缺失或重复的微阵列分析是正常的。因此,没有足够的证据来建立分子诊断。为了进一步探索数据并进行额外的调查，患者随后被纳入印第安纳大学医学院(IUSM)的未确诊罕见病诊所(URDC).URDC的调查人员对ES原始数据进行了重新分析，揭示了父系遗传的DYNC2H1深内含子变体c.10606-14A>G，预测会产生一个强大的隐性受体剪接位点。此外,成纤维细胞的RNA测序表明,预测内含子部分保留会导致提前终止密码子和无义介导的mRNA衰减(NMD).液滴数字RT-PCR(RT-ddPCR)显示DYNCH2H1mRNA水平显著降低74%。因此,内含子变异体随后被重新分类为可能的致病性,从而对该患者进行了明确的临床和遗传学诊断.ES和成纤维细胞mRNA实验的重新分析证实了剪接变体的致病性，以补充原始ES或CMA报告中未揭示的关键信息。NICU和URDC的合作结束了这个家庭的诊断之旅；此外，产前诊断母亲当前怀孕的可能性强调了其重要性。
