Child Kidney Dis.  2024 Feb;28(1):8-15. 10.3339/ckd.24.005.

Navigating the landscape of clinical genetic testing: insights and challenges in rare disease diagnostics

• Kim SY

• KMID: 2553175
• DOI: http://doi.org/10.3339/ckd.24.005

Abstract

With the rapid evolution of diagnostic tools, particularly next-generation sequencing, the identification of genetic diseases, predominantly those with pediatric-onset, has significantly advanced. However, this progress presents challenges that span from selecting appropriate tests to the final interpretation of results. This review examines various genetic testing methodologies, each with specific indications and characteristics, emphasizing the importance of selecting the appropriate genetic test in clinical practice, taking into account factors like detection range, cost, turnaround time, and specificity of the clinical diagnosis. Interpretation of variants has become more challenging, often requiring further validation and significant resource allocation. Laboratories primarily classify variants based on the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science guidelines, however, this process has limitations. This review underscores the critical role of clinicians in matching patient phenotypes with reported genes/variants and considering additional factors such as variable expressivity, disease pleiotropy, and incomplete penetrance. These considerations should be aligned with specific gene-disease characteristics and segregation results based on an extended pedigree. In conclusion, this review aims to enhance understanding of the complexities of clinical genetic testing, advocating for a multidisciplinary approach to ensure accurate diagnosis and effective management of rare genetic diseases.

Keyword

Genetic diseases; Genetic testing; Rare diseases

Figure

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  Fig. 1. Conceptual representation of expressivity, pleiotropy, and penetrance in autosomal dominant genetic disorders. (A) A pedigree displaying an autosomal dominant genetic with varying levels of disease expressivity among family members. (B) A pedigree illustrating an autosomal dominant genetic disorder demonstrating disease pleiotropy within family members. (C) A pedigree of autosomal dominant genetic disorder exhibiting complete penetrance. (D) A pedigree of autosomal dominant genetic disorder exhibiting incomplete penetrance. Mut, mutation.

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  Fig. 2. Physician’s guide to genetic testing in rare diseases.

Reference

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