Orphanet Journal of Rare Diseases | Whole-Exome Sequencing Reveals Clinical and Genetic Spectrum of Dual Rare Genetic Diseases in Children

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This study reveals the high prevalence of dual molecular diagnoses in children with complex phenotypes, suggesting that clinical diagnosis of rare diseases must move beyond single-gene thinking and utilize multi-omics strategies to analyze the additive effects of genetic variations.

 

Overview

This article, titled "Clinical and genetic spectrum of dual rare genetic diseases revealed by whole-exome sequencing in 14 pediatric patients," published in the Orphanet Journal of Rare Diseases, systematically explores 14 cases of dual molecular diagnoses identified via Whole-Exome Sequencing (WES) among 872 children suspected of having rare genetic disorders. The article details the clinical phenotypic characteristics, types of genetic variations, and their combination patterns in these cases, emphasizing the importance of identifying polygenic pathogenic mechanisms in complex phenotypes.

Background Knowledge

1. The pain point in rare diseases addressed by this study is that traditional Mendelian genetic models often assume a single genetic variation can explain the patient's phenotype, leading to missed or misdiagnoses in many children with complex, atypical, or overlapping phenotypes. 2. The current bottleneck in genetic diagnosis research is that conventional detection methods struggle to simultaneously capture multiple variation types such as Single Nucleotide Variants (SNV), Copy Number Variants (CNV), Uniparental Disomy (UPD), and mosaicism, lacking deep understanding of dual pathogenic mechanisms. 3. The entry point of this topic lies in utilizing high-throughput WES technology, which not only detects point mutations but also synchronously analyzes structural variations, thereby revealing the genetic basis of co-occurring rare diseases such as Angelman syndrome and Polycystic Kidney Disease, offering a new perspective for precision medicine.

 

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Research Methods and Core Experiments

The authors retrospectively analyzed WES data from families or probands of 872 pediatric patients between 2019 and 2025. The study used the IDT xGen Exome Research Panel v2.0 capture kit for deep sequencing (≥100×) on the BGI-T7 platform, and classified variant pathogenicity according to ACMG guidelines. The key evidence lies in confirming via Trio-WES combined with family validation that 14 patients simultaneously carried two independent pathogenic or likely pathogenic variants, each explaining part of the clinical phenotype. For instance, Patient 5 was found to have paternal uniparental disomy of chromosome 15 (causing Angelman syndrome) and a frameshift mutation in the PKD1 gene (causing Polycystic Kidney Disease), perfectly explaining their dual phenotype of developmental delay and renal cysts.

Key Conclusions and Perspectives

• Data Finding: Among confirmed rare disease patients, approximately 3.8% have dual molecular diagnoses, with 85.7% following an autosomal dominant inheritance pattern and 57.14% involving de novo variants. The guidance for subsequent clinical diagnostic strategies is that when facing complex phenotypes involving multiple systems that cannot be explained by a single gene, the possibility of dual diagnosis must be prioritized.
• Data Finding: 42.9% of dual diagnosis cases involve combinations of SNVs with other variation types (such as exon deletions, CNVs, UPD), and 2 mosaic variants were detected (DVL1 and NR0B1). The guidance for subsequent experimental directions is that WES technology possesses the advantage of synchronously detecting multiple variation types, making it the preferred tool for deciphering complex genetic mechanisms.
• Data Finding: 85.7% of dual diagnosis cases exhibit overlapping phenotypes, while only 14.3% show distinct phenotypes. Involved targets include ARID2, KIDINS220, PKD1, etc., where mutations cause phenotypes with overlaps in neurodevelopment and facial features. The guidance for subsequent mechanism research is the need to deeply explore interactions between different gene pathways to distinguish whether phenotype overlap stems from synergistic gene function or independent pathogenicity.

Research Significance and Outlook

From a research perspective, this finding has profound implications for rare disease drug development, suggesting that future targeted therapies must consider drug interactions and phenotype modifications within a multi-gene background. For clinical monitoring, early identification of dual diagnoses helps formulate more precise follow-up plans, especially for cases with mosaic characteristics. Furthermore, this study provides new ideas for disease modeling; when constructing animal models, one should not be limited to single-gene knockouts but explore double-gene modified models to simulate real-world complex clinical phenotypes.

 

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Conclusion

This study confirms through large-scale cohort analysis that dual molecular diagnoses are not rare coincidences but an不可忽视 genetic pattern in childhood complex rare diseases. Approximately 3.8% of confirmed pediatric patients harbor two independent pathogenic gene variants, often involving de novo dominant mutations and combinations of various variation types. This discovery breaks the limitations of traditional single-gene diagnosis, emphasizing the core advantages of whole-exome sequencing in synchronously detecting point mutations, structural variations, and mosaicism. For clinicians, facing children with overlapping phenotypes or those unexplainable by a single disease, active initiation of dual diagnosis screening is essential to avoid missed diagnoses and optimize genetic counseling. From the perspective of translation from laboratory to clinic, precisely identifying dual pathogenic mechanisms is the cornerstone of building a comprehensive rare disease care system; it not only improves diagnostic rates but also lays a solid foundation for developing personalized treatment strategies and deeply understanding multi-gene interaction mechanisms.

 

Minjun Zhao, Fuwei Li, Xiangpeng Lu, Hong Zheng, and Xilong Du. Clinical and genetic spectrum of dual rare genetic diseases revealed by whole-exome sequencing in 14 pediatric patients. Orphanet Journal of Rare Diseases.