ORIGINALREVIEW RESEARCH ClinicalClinical Medicine Medicine 2019 2017 Vol Vol 19, 17, No No 1: 6:30–6 30–8 T h e u t i l i t y o f p h e n o m i c s i n d i a g n o s i s o f i n h e r i t e d metabolic disorders Authors: J o y e e t a R a h m a n A a n d S h a m i m a R a h m a n B Inherited metabolic disorders (IMDs) are debilitating inherited and psychological implications for affected patients and diseases, with phenotypic, biochemical and genetic hetero- their families (Fig 1 ). Despite their severity, several IMDs are geneity, frequently leading to prolonged diagnostic odysseys. amenable to clinical intervention such as dietary modification, Mitochondrial disorders represent one of the most severe administration of metabolites, or enzyme replacement therapy, classes of IMDs, wherein defects in >350 genes lead to multi- which reduce mortality and morbidity and improve quality ABSTRACT system disease. Diagnostic rates have improved considerably of life. 4 Unfortunately, patients with IMDs often undergo following the adoption of next-generation sequencing (NGS) prolonged diagnostic odysseys because of the complexity of technologies, but are still far from perfect. Phenomic annota- the clinical presentations and the underlying pathobiology tion is an emerging concept which is being utilised to enhance typically associated with these disorders. A lack of distinguishing interpretation of NGS results. To test whether phenomic cor- features, non-standardised newborn screening programmes, and relations have utility in mitochondrial disease and IMDs, we a knowledge gap between front-line clinicians and metabolic created a gene-to-phenotype interaction network with search- experts are all obstacles to obtaining specific diagnoses. The able elements, for Leigh syndrome, a frequently observed genetic heterogeneity of IMDs is another challenging factor in paediatric mitochondrial disorder. The Leigh Map comprises that the most common groups of IMDs may be causally linked data on 92 genes and 275 phenotypes standardised in human to several hundred gene defects. These include mitochondrial phenotype ontology terms, with 80% predictive accuracy. This disorders, congenital disorders of glycosylation, and lysosomal commentary highlights the usefulness of the Leigh Map and storage disorders.3,5,6 similar resources and the challenges associated with integrat- In recent years the use of next-generation sequencing (NGS) ing phenomic technologies into clinical practice. technologies has helped to improve the diagnostic rate of IMDs and has exponentially increased the discovery rate of novel K E Y W O R D S : Mitochondrial disease , inherited metabolic disorders , causative gene mutations. 7 As NGS is increasingly becoming less rare disease , phenomics , Leigh syndrome expensive and more rapid, it is unsurprising that it is emerging as the preferred method of genetic diagnosis in many centres around the world. Furthermore, the use of NGS can in many cases avoid the need for invasive diagnostic tests such as muscle or liver biopsy, Introduction limiting the exposure of vulnerable patients, especially children, to Inherited metabolic disorders (IMDs) collectively represent general anaesthesia, which in some cases may trigger metabolic one of the most common groups of Mendelian diseases, decompensation. NGS, however, is not without its challenges, despite being individually rare (<1:2000) or ultra-rare disorders particularly when it comes to prioritising and analysing variants (<1:2,000,000).1 Many genetic defects underpinning IMDs are of unknown significance (VUS) or candidate disease genes for enzyme deficiencies within vital biosynthetic and metabolic potential differential diagnosis. Variant annotation challenges are pathways. However, IMDs are increasingly recognised to include amplified in those disorders in which there is significant phenotypic defects of structural proteins, trafficking proteins, chaperones heterogeneity. Furthermore, it may be labour intensive and time and other regulatory proteins pertaining to a metabolic process. 2 consuming to comb through knowledge bases or the compendium IMDs may be associated with debilitating and often fatal of literature to determine whether or not a variant is pathogenic. phenotypic presentations including epilepsy, intellectual disability, The use of phenomics, that is a complete characterisation of cardiomyopathy, liver failure, myopathy, and immunodeficiency. 3,4 (preferably standardised) phenotypic manifestations associated A crucial step in the clinical management of IMDs is obtaining with a particular gene defect or IMD could have utility in 8–10 a definitive genetic diagnosis, which has clinical, therapeutic, improving the diagnostic rate of difficult-to-diagnose IMDs. Comprehensive knowledge bases with searchable elements and user-friendly interfaces are cost-effective and potentially efficacious additions to enhance the interpretation of NGS findings and can Authors: APhD student, UCL Great Ormond Street Institute of Child have secondary benefits as clinical management tools. Health, London, UK ; B professor of paediatric metabolic medicine, Mitochondrial disorders are among the most severe metabolic UCL Great Ormond Street Institute of Child Health, London, UK disorders wherein patients suffer from multi-systemic phenotypes, 30 © Royal College of Physicians 2019. All rights reserved. CMJv19n1-ShamimaRahman.indd 30 1/4/19 11:04 PM Phenomics in inherited metabolic disorders Paent with clinical suspicion of an inherited metabolic disorder HP: 0002415 HP: 0001252 HP: 0001263 HP: 0001639 HP: 0004415 HP: 0001399 HP: 0002240 Next-generaon Phenomic resources sequencing Phenotyping SURF1 POLG HP: 0002415 PDHX HP: 0001263 RRM2B ALG9 ClinVar HP: 0004415 RTX1 GLA HP: 0001639 NPC1 OMIM BTD Predicve tools Knowledge bases Genec Fig 1. The utility of phenomics in the diagnosis inherited metabolic disease clinic. The use of phenomics resources, includ- managementClinical ing predictive tools and rare disease knowledge bases can assist in obtaining Benefit for a defi nitive genetic diagnosis when used families in conjunction with next-generation sequencing tests such as whole exome Treatment Genec or whole genome sequencing. Obtaining Dietary restricon counselling a genetic diagnosis improves patient care by providing treatment options, Pharmacovigilance Carrier improved pharmacovigilance, and pre- screening ventative screening for at-risk disorders Further tesng such as cancer and neurodegenerative Educaon Preventave diseases. In addition, genetic diagnoses provide benefi ts to the family by facilitat- screening Psychological benefit ing accurate genetic counselling, as well as providing psychological benefi t to parents. often resulting in early death. Primary mitochondrial disorders mitochondrial lipid homeostasis. 3 Large-scale NGS gene panel are described as those which primarily or secondarily cause studies currently place the diagnostic rate of mitochondrial dysfunction of oxidative phosphorylation (OXPHOS) or other disorders between ∼35–60%. 11,12 The genetic heterogeneity of elements of mitochondria such as defects in vitamin and cofactor mitochondrial disorders and ongoing discovery of novel disease metabolism, aberrant mitochondrial dynamics, and abnormal genes are caveats which can deem whole exome sequence (WES) © Royal College of Physicians 2019. All rights reserved. 31 CMJv19n1-ShamimaRahman.indd 31 1/4/19 11:04 PM Joyeeta Rahman and Shamima Rahman data unsuitable to provide clinicians with enough certainty for a inheritance, patient demographics, magnetic resonance imaging definitive diagnosis in all cases. (MRI) findings, and links to external genetic and scientific We hypothesised that the use of phenomic annotation databases. Furthermore, each genetic element in the Leigh Map in mitochondrial disorders could be of diagnostic utility. has an accompanying sub-map which documents all phenotypes Mitochondrial disorders are characterised by extreme phenotypic associated with that particular gene defect. Phenotypes are heterogeneity, affecting virtually any organ or system, seemingly annotated in human phenotypic ontology (HPO) terms, a system in any combination. However, by documenting the phenotypes for standardising clinical features that are synonyms. 16 For of reported patients with mitochondrial disease and mapping example, ‘decreased muscle tone’ or ‘floppiness’ can be expressed the associations to causative genes, any emerging patterns can as one HPO term ‘muscular hypotonia’ (HP: 0001252). In total, the enhance the interpretation of NGS to expedite genetic diagnoses Leigh Map currently comprises 236 HPO phenotypes (Fig 2 ). for patients and elucidate novel gene-to-phenotype correlations. Content query is another Google Maps feature which is To test this strategy, we constructed a novel gene-to-phenotype embedded within MINERVA. The Leigh Map features more interaction network using Leigh syndrome as a prototype. than 1700 gene-to-phenotype interactions, all of which can be queried by the user using the search function. Querying the name Leigh Map: a case for phenomics-based tools in or HPO number of a particular phenotype will result in a list of inherited metabolic disorders genes with which that phenotype has been associated. The Leigh Map supports the query of multiple phenotypes simultaneously, Layout and validation of the Leigh Map therefore this feature can be used in a diagnostic setting to We chose Leigh syndrome as our prototype disorder because elucidate causative disease genes. Conversely,