Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder due to defects in the branched‐chain α‐ketoacid dehydrogenase complex (BCKDC). MSUD varies in severity and its clinical spectrum is quite broad, ranging from mild to severe phenotypes. Thirty‐three MSUD patients were recruited into this study for molecular genetic variant profiling and genotype–phenotype correlation. Except for one patient, all other patients presented with the classic neonatal form of the disease. Seventeen different variants were detected where nine were novel. The detected variants spanned across the entire BCKDHA, BCKDHB and DBT genes. All variants were in homozygous forms. The commonest alterations were nonsense and frameshift variants, followed by missense variants. For the prediction of variant's pathogenicity, we used molecular modeling and several in silico tools including SIFT, Polyphen2, Condel, and Provean. In addition, six other tools were used for the prediction of the conservation of the variants' sites including Eigen‐PC, GERP++, SiPhy, PhastCons vertebrates and primates, and PhyloP100 rank scores. Herein, we presented a comprehensive characterization of a large cohort of patients with MSUD. The clinical severity of the variants' phenotypes was well correlated with the genotypes. The study underscores the importance of the use of in silico analysis of MSUD genotypes for the prediction of the clinical outcomes in patients with MSUD.

中文翻译：

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33枫糖浆尿病患者的基因型与表型相关性。

枫糖浆尿病（MSUD）是一种罕见的常染色体隐性遗传性疾病，归因于支链α-酮酸脱氢酶复合物（BCKDC）的缺陷。MSUD的严重程度各不相同，其临床范围也很广，从轻度到重度表型不等。本研究招募了33例MSUD患者，以进行分子遗传变异分析和基因型与表型的相关性。除一名患者外，其他所有患者均出现该疾病的经典新生儿形式。检测到十七种不同的变体，其中九种是新颖的。检测到的变异涵盖了整个BCKDHA，BCKDHB和DBT基因。所有变体均为纯合形式。最常见的变化是无意义和移码变体，其次是错义变体。为了预测变体的致病性，我们使用了分子建模和一些计算机软件工具，包括SIFT，Polyphen2，Condel和Provean。此外，还使用其他六个工具来预测变体位点的保守性，包括本征PC，GERP ++，SiPhy，PhastCons脊椎动物和灵长类动物以及PhyloP100等级得分。在这里，我们介绍了一大批MSUD患者的综合特征。变异体表型的临床严重程度与基因型密切相关。这项研究强调了对MSUD基因型进行计算机分析的重要性，以预测MSUD患者的临床结局。