A holistic approach to maximise diagnostic output in trio exome sequencing

Abstract

IntroductionRare genetic diseases are a major cause for severe illness in children. Whole exome sequencing (WES) is a powerful tool for identifying genetic causes of rare diseases. For a better and faster assessment of the vast number of variants that are identified in the index patient in WES, parental sequencing can be applied (“trio WES”).MethodsWe assessed the diagnostic rate of routine trio WES including analysis of copy number variants in 224 pediatric patients during an evaluation period of three years.ResultsTrio WES provided a diagnosis in 67 (30%) of all 224 analysed children. The turnaround time of trio WES analysis has been reduced significantly from 41 days in 2019 to 23 days in 2021. Copy number variants could be identified to be causative in 10 cases (4.5%), underlying the importance of copy number variant analysis. Variants in three genes which were previously not associated with a clinical condition (GAD1, TMEM222 and ZNFX1) were identified using the matching tool GeneMatcher and were part of the first description of a new syndrome.DiscussionTrio WES has proven to have a high diagnostic yield and to shorten the process of identifying the correct diagnosis in paediatric patients. Re-evaluation of all 224 trio WES 1–3 years after initial analysis did not establish new diagnoses. Initiating (trio) WES as a first-tier diagnostics including copy number variant detection should be considered as early as possible, especially for children treated in ICU, if a monogenetic disease is suspected.

Current genetic diagnostics in inborn errors of immunity

“…Simultaneous genetic analysis of the patient and their parents [NGS-based Trio (Trio WES or Trio-WGS)] is a useful approach to speed up the process of making a precise genetic diagnosis ( 54 ). This is because the parental data and segregation information for each variant are immediately available, facilitating clinical interpretation of the variants.…”

Early-Onset Ovarian Cancer <30 Years: What Do We Know about Its Genetic Predisposition?

“…The low frequency of de novo mutations among OC patients may have been biased by the HBOC genetic testing criteria, which used to prioritize patients with strongly positive family histories [100]. As early-onset OC patients lack a strong family cancer history [8], the de novo or compound heterozygous OC-predisposition mutations may be under-reported, and their identification, e.g., using a trio WES (analysis of the patient + her parents) similar to other rare childhood/early-onset diseases [101] may help to uncover the underlying genetic causes.…”

Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype

“…To date, >50 genes have been described with well-known association to characteristic clinical symptoms and ultrastructural defects in TEM, also referred to as genotype-phenotype correlation [1,9]. Genetic analysis by next generation sequencing (NGS) is an expeditious diagnostic that is increasingly used in many research settings [4], but also in the routine work-up of orphan diseases in Germany in the past few years [10]. However, it reveals inconclusive results in approximately 30% of patients with a clinical phenotype compatible with PCD, due to either variants of uncertain significance (VUS; class 3 according to American College of Medical Genetics [ACMG]) in established PCD genes or variants in candidate genes of uncertain significance with assumed but unconfirmed association to motile ciliopathies [1,8].…”