Are Inherited Metabolic Disorders More Common and Less Predictable Than We Thought?

Area of Science:

• Genomics
• Medical Genetics
• Public Health

Background:

• Genotype-first approaches are redefining the understanding of inherited metabolic disorders (IMDs).
• Large-scale genomic data from healthy populations and clinical testing uncover previously unrecognized 'genotype positive' IMD cases.

Purpose of the Study:

• To discuss the implications of genotype-first findings for IMD prevalence and penetrance.
• To evaluate the utility of genomic sequencing as a public health screening tool for newborns.

Main Methods:

• Analysis of large-scale genomic data from healthy newborns and adult biobanks.
• Review of clinical testing data, including reproductive carrier screening and secondary findings from exome/genome sequencing.

Main Results:

• Genomic sequencing identifies a new category of genotype-positive IMD cases previously missed by clinicians and public health.
• Prevalence and penetrance data challenge traditional assumptions about IMDs in apparently healthy individuals.

Conclusions:

• Genomic sequencing offers potential for early detection of treatable IMDs and risk identification.
• Widespread genomic data necessitates careful consideration, as variants don't always require intervention, impacting screening tool utility.