An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients

Eur J Hum Genet. 2022 Sep;30(9):1029-1035. doi: 10.1038/s41431-022-01119-5.

PMID: 35614200

Ligia S Almeida, Catarina Pereira, Ruxandra Aanicai

Highlights: The aim of this study is to present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs).

Abstract

Objective: To share our knowledge of the effectiveness of a multiomic approach, which combines genetic and biochemical testing as a primary diagnostic method for those with hereditary metabolic disorders (IMDs).

Methods: A panel of 206 genes with single nucleotide and copy number variant (SNV/CNV) identification, semi-automatic variant filtering, and reflex biochemical testing were used to evaluate a cohort of 3720 patients from 62 different countries (25 assays).

Results: An accurate genetic diagnosis was made in 1389 patients (37%). Within this cohort, patients from Asia (57.5%, primarily from Pakistan) had the highest diagnostic yield. 40 CNVs and 701 pathogenic/likely pathogenic distinct SNVs were found in total. The results of the biochemical tests guided variant classification and reporting in 620 cases. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We demonstrate that integrated genetic and biochemical testing produced a high diagnostic yield (37%), which is comparable to exome/genome sequencing, and aided the determination of the clinical importance of the variations. Furthermore, up to 43% of these patients (n = 610) could gain from receiving medical care (e.g., enzyme replacement therapy).

Conclusion: This multiomic strategy is a special and powerful tool for the genetic diagnosis of IMDs.

Keywords: inherited metabolic disorders, multiomic approach, genetic diagnosis