Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149 Trieste, Italy.
Institute for Maternal and Child Health-I.R.C.C.S. "Burlo Garofolo", 34137 Trieste, Italy.
Genes (Basel). 2022 Nov 3;13(11):2023. doi: 10.3390/genes13112023.
Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report the identification of double genetic disorders in a series of patients with complex clinical features. In the last 24 months, 342 syndromic patients have been recruited and clinically characterised. Whole Exome Sequencing analysis has been performed on the proband and on both parents and identified seven patients affected by a dual molecular diagnosis. Upon a detailed evaluation of both their clinical and molecular features, subjects are able to be divided into two groups: (A) five patients who present distinct phenotypes, due to each of the two different underlying genetic diseases; (B) two patients with overlapping clinical features that may be underpinned by both the identified genetic variations. Notably, only in one case a multilocus genomic variation was already suspected during the clinical evaluation. Overall, our findings highlight how dual molecular diagnoses represent a challenging model of complex inheritance that should always be considered whenever a patient shows atypical clinical features. Indeed, an accurate genetic characterisation is of the utmost importance to provide patients with a personalised and safe clinical management.
双分子诊断定义为存在两个不同的、独立分离的基因座上的致病性变异，导致两种不同的孟德尔疾病。在这项研究中，我们报告了一系列具有复杂临床特征的患者中双重遗传疾病的鉴定。在过去的 24 个月中，已经招募了 342 名综合征患者并进行了临床特征分析。对先证者及其父母进行了全外显子组测序分析，发现了 7 名患有双重分子诊断的患者。通过对他们的临床和分子特征进行详细评估，这些患者可分为两组：(A)5 名患者由于两种不同的基础遗传疾病而表现出不同的表型；(B)2 名患者具有重叠的临床特征，可能由已鉴定的遗传变异共同引起。值得注意的是，仅在一个病例中，在临床评估期间已经怀疑存在多基因座基因组变异。总体而言，我们的研究结果强调了双分子诊断是一种具有挑战性的复杂遗传模式，当患者表现出非典型临床特征时，应始终考虑这一模式。事实上，准确的遗传特征分析对于为患者提供个性化和安全的临床管理至关重要。
