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Table 4 Key features of diagnostic methods for ultra-rare IEMs: NP-C as an example

From: Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C?

Method Examples for NP-C Key features
Biomarkers • Oxysterols (C-triol, 7-KC) • Advantages
• Lysosphingolipids (Lyso-SM-509, lysosphingomyelin) • Objective, quantitative methodology
• Rapid, practical and cost-effective*
• Bile acids (3β,5α,6β-trihydroxycholanic acid) • Biomaterials easily accessible and transportable
• Disadvantages
• Available for relatively few ultra-rare IEMs
• Requires that disease of interest is already in differential diagnosis
• Patient heterogeneity can present a hurdle, with possible false-negatives/positives
Genetic analysis • Single-gene sequencing • Advantages
• Gene panel (e.g., ataxia panel) • Objective screening data
• WES • No requirement for differential diagnosis
• WGS • Can provide information on diseases not in differential diagnosis
• Might indicate alternate molecular diagnosis
• Disadvantages
• Not yet widely available without appreciable costs
• Limited information on pathogenicity of unique gene variants (potential false negatives and false positives)
• Challenging management of VUS in symptomatic patients without biochemical marker findings
• Management of incidental findings
Clinical assessment • Multi-disciplinary assessment of clinical manifestations • Advantages
• Widespread availability of professionals capable of carrying out clinical assessment
• Differential diagnosis
• Assessment of clinical picture from patient files • Traditional approach set up in healthcare systems
• Disadvantages
• Can be time consuming
• NP-C SI • Require multiple inter-disciplinary referrals
• Variation in quality: assessments not based on validated clinical tools require IEM expert knowledge to detect disease
• Non detection of atypical/non-standard or early-stage presentations due to non-specific clinical phenotypes
• Do not deliver diagnosis per se although diagnoses can be confirmed using biomarkers and/or genetic methods
  1. aCost effectiveness depending on local infrastructure and/or geographical region; 7-KC 7-ketocholesterol, C-triol cholestane-3β,5α,6β-triol, NP-C SI NP-C suspicion index, VUS variant of unknown significance, WES whole-exome sequencing, WGS whole-genome sequencing