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Application of next-generation sequencing in the diagnosis of inherited metabolic disorders in Iran: An 11-year overview

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Inherited metabolic disorders (IMD), a diverse group of disorders with biochemical pathways alterations, are individually rare but collectively common in more than 1:800 individuals. The most recent classification encompasses 24 main IMD categories. Many IMDs are diagnosed with milder symptoms during adolescence and adulthood, although severe neonatal forms are recognized. These disorders can present in a wide range of clinical presentations. Next-generation sequencing (NGS) technology enables the simultaneous sequencing of numerous genes with high precision and reliability. Here, we report our findings in the investigation of variations in metabolic genes in individuals who underwent whole-exome sequencing (WES), targeted NGS panels, and Sanger sequencing.

Methods:
Between 2013 and 2024, three thousand, eight hundred eleven individuals were referred by clinicians to the Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran, for clinical WES and targeted NGS panels(n=3502) testings. Additionally, patients with highly suspicious for specific metabolic disorders were referred to be subjected to Sanger sequencing (n=309). For most NGS cases, exome capture was performed using the Twist Human Core Exome Kit (Twist Bioscience, San Francisco, CA, USA). Common genes potentially involved in metabolic pathways were selected based on the literature review.

 

Results:
Variants in metabolic genes were detected in (622/3502, 17.7%) individuals subjected to NGS testing, ranging from prenatal to adulthood. Parental consanguinity is presented in 75.7% of cases and a family history of affected siblings in 29.7%. Missense variants (45%) were the most common variants diagnosed in metabolic genes by NGS, followed by frameshift (24%), and stop gain (16%). According to the International Classification of Inherited Metabolic Disorders (ICIMD) group classification, the most commonly diagnosed groups of IMDs using the NGS technique were disorders of intermediary metabolism (136/384, 35.4%) and disorders of complex molecule and organelle metabolism (128/384, 33.3%), followed by the lipid metabolism and transport disorders at (32/384, 8.3%). The most prevalent genes in each group were TYR (9.5%), SPG11 (14.8%), and PLA2G6 (34.3%), respectively. In our study, abnormalities of the nervous system, homeostasis/metabolism, and musculature were the most frequently observed phenotypes.

For Sanger sequencing, the diagnostic rate was (154/309, 49%%). The most commonly referred condition was phenylketonuria (PKU) at 16.5% (51/309), followed by Wilson's disease (40/309, 13%), and adrenoleukodystrophy (21/309, 6.7%), with the diagnostic rate of (42/51, 82%), (14/40, 35%), and (5/21 23.8%), respectively.

Conclusion:
Recent advancements in diagnostic methods, particularly NGS, have greatly improved the identification of causative genes in these conditions. Our results show the impact of using NGS methods on identifying the underlying causative gene in IMD, particularly in a country with a high rate of consanguineous marriage. By understanding the causative genes and variants, we could get great insight into the disease and get help from it in treating the patients. Timely and accurate diagnosis is crucial, as many of these disorders are treatable, and early detection can significantly improve outcomes for patients and their families. Clinical diagnosis, along with targeted genetic testing using methods like Sanger sequencing, can help achieve this goal more effectively.

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