Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

Park²,

et al. 2019

Preprint

BackgroundA substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.MethodsGenetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.ResultsDisease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.ConclusionsWe suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

Section: Discussionsupporting

confidence: 87%

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

Park²,

et al. 2019

Preprint

“…A change of patient medication, either initiation of a new treatment or halting of an existing one, was specifically reported in 22 studies. 8,[15][16][17][18]20,22,23,[26][27][28][29][30][31][32][33][34][35][36][37][38][39] For example, Anazi et al reported a patient with ID who was homozygous for a truncating pathogenic variant in SLC39A14 that causes a potentially treatable form of hypermanganesemia, who was started on chelation therapy, resulting in improved manganese levels. 17 In a case series of patients with presumed neurogenetic disorders and DD/ID from Argentina, 10% (4/ 40) underwent a trial of new medication following ES, including a trial of L-Dopa in a patient with paraplegia and ID who had pathogenic variants in SPG11 and a trial of acetazolamide and fampridine in a patient with a pathogenic variant in KCNA2.…”

Section: Medication and Dietary Managementmentioning

confidence: 99%

“…39 Alterations to a patient's existing diet were mentioned in nine studies. 8,23,26,27,30,31,33,40,41 In a case series of 43 French patients with dysmorphic features and neurodevelopmental disorders including severe to profound ID, a patient diagnosed with compound heterozygous pathogenic variants in ADCK3 was diagnosed with coenzyme Q10 deficiency. Coenzyme Q10 supplementation and a ketogenic diet were introduced following ES results.…”

Section: Medication and Dietary Managementmentioning

confidence: 99%

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability

Malinowski¹,

Miller

Demmer

et al. 2020

Genetics in Medicine

A full list of authors and affiliations appears at the end of the paper.Disclaimer: The ACMG has recruited expert panels, chosen for their scientific and clinical expertise, to conduct systematic evidence reviews (SERs) to support the development of clinical practice guidelines. An SER focuses on a specific scientific question and then identifies, analyzes and summarizes the findings of relevant studies. ACMG SERs are provided primarily as educational resources for medical geneticists and other clinicians to help them provide quality medical services. They should not be considered inclusive of all relevant information on the topic reviewed. Reliance on this SER is completely voluntary and does not necessarily assure a successful medical outcome. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this SER. Clinicians also are advised to take notice of the date this SER was published, and to consider other medical and scientific information that becomes available after that date.

“…3,6 Note that these studies have already identified and excluded patients with the more common nucleotide repeat expansion diseases.…”

Section: Clinical Exome Sequencingmentioning

confidence: 99%

“…Simultaneous interrogation of multiple genes using clinical exome sequencing or a large multigene panel is increasingly reported as an efficient method for identifying a diagnosis in individuals with ataxia. [3][4][5] However, the most common causes of hereditary ataxia are due to nucleotide repeat expansions that would not be identified by these sequencing techniques.…”

mentioning

confidence: 99%

Molecular genetic testing for hereditary ataxia

Wallace

Bird

2018

Neur Clin Pract

Purpose of reviewBecause of extensive clinical overlap among many forms of hereditary ataxia, molecular genetic testing is often required to establish a diagnosis. Interrogation of multiple genes has become a popular diagnostic approach as the cost of sequence analysis has decreased and the number of genes associated with overlapping phenotypes has increased. We describe the benefits and limitations of molecular genetic tests commonly used to determine the etiology of hereditary ataxia.Recent findingsThere are more than 300 hereditary disorders associated with ataxia. The most common causes of hereditary ataxia are expansion of nucleotide repeats within 7 genes: ATXN1, ATXN2, ATXN3, ATXN7, ATXN8, CACNA1A (spinocerebellar ataxia type 6), and FXN (Friedreich ataxia). Recent reports describing the use of clinical exome sequencing to identify causes of hereditary ataxia may lead neurologists to start their clinical investigation with a less sensitive molecular test providing a misleading “negative” result.SummaryThe majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.