PGmax^TM - Comprehensive Inherited Metabolic Disorders and Mitochondrial Disorders (Nuclear Genes only) Panel

Inherited metabolic disorders (IMDs) and mitochondrial disorders associated with defects in nuclear-encoded mitochondrial genes are clinically and genetically heterogeneous disorders. Phenotypes range in severity and progression and can involve single or multiple organ systems. Currently, it is suggested that any condition in which impairment of a specific biochemical pathway or enzyme function is intrinsic to the pathophysiology of the disease be considered an IMD, regardless of whether it is associated with specific abnormalities in biochemical tests (Morava et al. 2015. PubMed ID: 26420281; Ferreira et al. 2019. PubMed ID: 29884839). Mitochondrial disorders, or oxidative phosphorylation (OXPHOS) disorders, are characterized by reduced activity of one (isolated) or more (combined) mitochondrial respiratory chain enzyme complexes (Ghezzi and Zeviani. 2018. PubMed ID: 30030362). Based on a nosology first proposed in 2019 and an International Classification of IMDs (ICIMD) published in 2021, nearly 1,500 genes divided into more than 100 groups are currently associated with IMDs and nuclear-encoded mitochondrial disorders (Ferreira et al. 2019. PubMed ID: 29884839; Saudubray et al. 2019. PubMed ID: 30883825; Ferreira et al. 2021. PubMed ID: 33340416), with certainly more to be discovered. Online resources with current data from the nosology and ICIMD efforts are available to allow one to explore the various IMDs and OXPHOS disorders by searching classification tables and specific disorders (Nosology of Inborn Errors of Metabolism at http://iembase.org/classification/n-search.asp; International Classification of Inherited Metabolic Disorders at http://www.icimd.org/).

This panel includes over 1,300 genes focusing on IMDs and OXPHOS disorders. Broadly, the IMDs included in this panel are divided into disorders affecting the following metabolic processes: amino acid, carbohydrate, peptide, amine, and fatty acid and ketone body metabolism; energy substrate metabolism, nuclear-encoded disorders of oxidative phosphorylation, mitochondrial cofactor biosynthesis, mitochondrial DNA maintenance and replication, and intermediary metabolism; lipid and lipoprotein, nucleotide and nucleic acid metabolism; tetrapyrrole metabolism, complex molecule degradation, vitamin and cofactor metabolism, trace element and metal metabolism, neurotransmitter metabolism, endocrine metabolic disorders, congenital disorders of glycosylation, and disorders of organelle biogenesis, dynamics and interactions. Furthermore, a variety of studies have been published focusing on IMDs with available treatment (Saudubray et al. 2006. PubMed ID: 16763886; Sirrs et al. 2013. PubMed ID: 24427801; Leach et al. 2014. PubMed ID: 25433678; van Karnebeek et al. 2018. PubMed ID: 30559706; Verheijen et al. 2020. PubMed ID: 31534212; Ondruskova et al. 2021. PubMed ID: 32991969; Hoytema van Konijnenburg et al. 2021. PubMed ID: 33845862). The majority of the genes from those studies have been included in this panel.

Diagnosis of patients with IMDs or OXPHOS disorders may involve a variety of complimentary techniques, including classical biochemical laboratory tests, proteomics, lipidomics, glycomics, metabolomics, and molecular technologies including sequencing and copy number analysis (Morava et al. 2015. PubMed ID: 26420281).

This test includes genes on the current Nosology of Inborn Errors of Metabolism and ICIMD websites; as well as those identified through literature searches that have a reported association with IMDs.

Inherited metabolic disorders are genetically heterogenous. Disorders may be inherited in an autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) manner or may arise de novo. Causative variants may include missense, nonsense, frameshift, splicing, regulatory, or copy number alterations.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Due to the genetic heterogeneity of the disorders tested in this panel, the clinical sensitivity of this specific grouping of genes is difficult to estimate. We are currently unaware of any reports in the literature in which these genes have been sequenced together.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.0% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

The Comprehensive Inherited Metabolic Disorders and Mitochondrial Disorders (Nuclear Genes only) Panel is a phenotype-driven analysis and patient clinical information is required. This information can be submitted in the form of clinical notes or using our clinical phenotype checklist. For best results, we recommend including age of onset of symptoms, and if they are episodic, the frequency and duration of the episodes.

Reporting: Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype
• Variants in genes possibly associated with the provided phenotype

Of note, Next Generation Sequencing analysis of the SDHA gene is technically challenging due to the presence of segmental duplications and paralogy. Therefore, analysis of CNVs in this region is not included in this test.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).