P649: The clinical utility of genome sequencing in the molecular diagnosis of genes related to inborn errors of metabolism

Introduction: In the era of clinical and molecular genetics and genomics, disorders of inborn errors of metabolism (IEM) can no longer be considered limited to abnormalities in the synthesis or catabolism of molecules in pathways measurable in classical biochemical assays.Instead, they are defined as impairments of biochemical pathways intrinsically resulting in the pathophysiology of various diseases.A recent review highlighted prominent categories of IEM disorders, such as errors in the metabolism of nitrogen-containing compounds, disorders of glycosylation, disorders of vitamin metabolism, lysosomal storage disorders, disorders of sterol and steroid metabolism, peroxisomal disorders, disorders of metal metabolism, and mitochondrial-related disorders of energy metabolism.While IEM disorders are routinely diagnosed via biochemical testing, individuals with early onset of nonspecific phenotypes, unusual presentations, or multiple co-occurring genetic disorders may undergo extensive testing before receiving a diagnosis.The clinical utility of genome sequencing is quickly being realized for various indications, and this study focuses on a thorough investigation in the context of IEM diseases.Methods: Genome sequencing (GS) was performed on genomic DNA using 2X150bp reads by next-generation sequencing (NGS) at a mean coverage of 40X across the entire genome.A retrospective investigation of reported IEM-related genetic variants was conducted in a total of 3153 GS cases, with provided information on phenotypes, from a continuous period.The age of the probands ranged from newborn to 80 years.Results: Out of the 3153 cases, 368 (11.7%) reported IEM gene variants with diagnostic or potential diagnostic findings.Among the 1021 IEM genes investigated, 214 were reported in these cases.A total of 199 cases requested proband-only GS testing, while 169 cases received testing for the proband along with family members, such as trio testing.Diagnostic cases are defined as those with pathogenic/likely pathogenic (P/LP) variants reported, while potential diagnostic cases are defined as those with variants of uncertain significance (VUS) and/or P/LP variants reported.Among the 92 reported diagnostic cases, 42 were related to autosomal recessive (AR) disorders, 14 to autosomal dominant (AD) disorders, 27 to genes involving both dominant and recessive inheritance or semidominant (SD) disorders, and 9 to X-linked (XL) disorders.An additional 276 potential diagnostic cases were reported, including 95 related to AR disorders, 68 to AD disorders, 79 to ADAR/SD conditions, and 34 to XL disorders.Variants were reported with greater frequency in the following IEM-related genes: APOE, CPT2, G6PD, GABBR2, GRIN2A, GRIN2B, GRIN2D, HCFC1, IFIH1, ITPR1, LDLR, POLG, and VPS13B.Among all diagnostic/potential diagnostic cases, 39 UTR and deep intronic variants were reported, including 3 variants classified as P/LP.These variants are not usually detected by exome-based DNA sequencing.Conclusion: A wide spectrum of clinical symptoms in patients often leads to enigmas in clinical diagnosis, making genome-level molecular diagnosis a critical step in assisting the clinical world.The study of this large cohort of GS cases revealed that IEM disorders represent an important proportion of diseases that can be readily diagnosed at the molecular level by GS.GS testing for the proband with family members reduced the molecular diagnosis burden during the data analysis process compared to proband-only testing, especially for recessive conditions, which is the most common inheritance pattern for IEM disorders.Furthermore, disease-causing genetic variations can be identified more efficiently by GS compared to other large-scale genomic assays such as exome sequencing.In follow-up, the profile of molecular diagnosis of IEM disorders also helps the clinic gain a deeper understanding of the mechanisms and manifestations of these genetic diseases.