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<p>Inborn errors of metabolism (IEMs) are severe genetic disorders caused by disruptions in metabolic pathways, frequently presenting in early life. Exome (ES) and genome (GS) sequencing have revolutionized the diagnostic approach for Mendelian disorders. However, most studies evaluating the diagnostic yield of ES have focused on predominantly European ancestry populations, leaving significant gaps in understanding its efficacy across diverse ancestries. We evaluated the diagnostic yield of ES in a cohort of 845 newborns with clinically diagnosed IEMs through the California Department of Public Health’s Genetic Disease Screening Program (GDSP) and its relationship to genetic ancestry. Over 55% of this ancestrally diverse cohort was maternally reported as non-white/European. By estimating genetic ancestry from exome sequencing data, we assessed its relationship with ES diagnostic outcomes. Diagnostic yield by ES did not significantly differ by any genetic ancestry, supporting its equitable performance across all ancestries among these largely recessive disorders. Higher consanguinity coefficients were associated with increased homozygosity among exome-positive cases, without affecting diagnostic yield across genetic ancestries.</p>

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No association between genetic ancestry and exome sequencing-based diagnosis of inborn errors of metabolism

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月27日

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  • J. Najera,
  • Y. Mavura,
  • A. Adhikari,
  • M. Kvale,
  • R. C. Gallagher,
  • N. Risch

摘要

Inborn errors of metabolism (IEMs) are severe genetic disorders caused by disruptions in metabolic pathways, frequently presenting in early life. Exome (ES) and genome (GS) sequencing have revolutionized the diagnostic approach for Mendelian disorders. However, most studies evaluating the diagnostic yield of ES have focused on predominantly European ancestry populations, leaving significant gaps in understanding its efficacy across diverse ancestries. We evaluated the diagnostic yield of ES in a cohort of 845 newborns with clinically diagnosed IEMs through the California Department of Public Health’s Genetic Disease Screening Program (GDSP) and its relationship to genetic ancestry. Over 55% of this ancestrally diverse cohort was maternally reported as non-white/European. By estimating genetic ancestry from exome sequencing data, we assessed its relationship with ES diagnostic outcomes. Diagnostic yield by ES did not significantly differ by any genetic ancestry, supporting its equitable performance across all ancestries among these largely recessive disorders. Higher consanguinity coefficients were associated with increased homozygosity among exome-positive cases, without affecting diagnostic yield across genetic ancestries.