Next-generation sequencing (NGS)-based genetic testing using a combined panel-whole-exome sequencing (WES) approach may be a viable way of diagnosing genetic liver diseases such as Alagille syndrome (ALGS), according to an article published in The Journal of Pediatrics.

The study explored the diagnostic utility of combined advanced genetic analysis methods in 374 patients with suspected genetic liver disease who were referred to a major pediatric liver transplantation center between 2005 and 2021.

The researchers investigated 3 tiers: tier 1 was Sanger sequencing on SLC2SA13ATP8B1ABCB11ABCB4, and JAG1 genes, tier 2 was panel-based NGS, and tier 3 was WES analysis.  


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Of 175 patients subjected to Sanger sequencing, 38 (21.7%) were identified as carriers of pathogenic variants. Among 216 participants, including 39 tier 1-negative patients who received panel-based NGS, 60 patients (27.8%) were identified as carriers of pathogenic variants. Of 41 patients who received WES analysis, 20 (48.8%) were identified with a genetic diagnosis.

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Pathogenic variants were detected in 6 of 19 (31.6%) patients who tested negative in tier 2, while a higher detection rate was established in 14 of 22 (63.6%) patients with deteriorating or multiorgan disease receiving one-step WES.

The overall disease spectrum included 35 genetic defects. Moreover, 90% of identified genes belonged to the functional categories of small molecule metabolism, ciliopathy, bile duct development, and membrane transport.

“In patients without a clinical clue for a specific disease, panel-based NGS served as an excellent diagnostic tool,” Chen and colleagues concluded. “For institutions with readily available NGS capability and capacity, the panel NGS can replace single-gene Sanger sequencing as tier 1 test, to improve diagnostic efficacy and efficiency.”

“Finally, WES is the best choice for a precise diagnosis in patients with rapidly deteriorating disease and patients with multi-organ involvement. WES should also be considered in patients with protracted/progressive disease and for those who fail to achieve a definite diagnosis using an NGS panel or other diagnostic tools.”

The utility of advanced genetic analysis may be limited by the expensive equipment, high medical costs, as well as technique and expertise requirements.

Reference

Chen CB, Hsu JS, Chen PL, et al. Combining panel-based next-generation sequencing and exome sequencing for genetic liver diseases. J Pediatr. Published online April 3, 2023. doi:10.1016/j.jpeds.2023.113408