Background Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adult...

https://www.nejm.org/doi/suppl/10.1056/NEJMoa1806891/suppl_file/nejmoa1806891_appendix_1.pdf

Diagnostic Utility of Exome Sequencing for Kidney Disease

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition However, making a molecular diagnosis with current technologies and knowledge is often still a challenge Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease Importantly, for affected families, a better understanding of the genetic basis of rare disease translates to more accurate prognosis, management, surveillance and genetic advice; stimulates research into new therapies; and enables provision of better support

Paediatric genomics: diagnosing rare disease in children.

Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011–August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34–0.48, I2 = 44%) and WES (0.36, 95% CI 0.33–0.40, I2 = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08–0.12, I2 = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA (P < 0.0001, I2 = 13% and I2 = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA (P < 0.001, I2 = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62–2.56, I2 = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38–0.45, I2 = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27–0.31, I2 = 49%); this difference was significant among studies published in 2017 (P < .0001, I2 = 22% and I2 = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17–0.40, I2 = 54%) and WES (0.17, 95% CI 0.12–0.24, I2 = 76%) were higher than CMA (0.06, 95% CI 0.05–0.07, I2 = 42%); this difference was significant for WGS vs CMA (P < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.

/pdf/meta-analysis-of-the-diagnostic-and-clinical-utility-of-3pyogbt4gv.pdf

Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study.

Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).

Importance While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined. Objective To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants. Design, Setting, and Participants Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children’s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants. Main Outcomes and Measures Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders. Results The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling. Conclusions and Relevance Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

/pdf/use-of-exome-sequencing-for-infants-in-intensive-care-units-zxzprvb9c0.pdf

Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management

Epileptic encephalopathies (EEs) are severe brain disorders with excessive ictal (seizure) and interictal (electrographic epileptiform discharges) activity in developing brain which may result in progressive cognitive and neuropsychological deterioration. In contrast to regular epilepsy where the treatment goal is to prevent the seizure (ictal) recurrence, in patients with EE the goal is to treat both ictal as well as interictal activity to prevent further progression. With the introduction of genetic sequencing technologies over the past 20 years, there is growing recognition of the genetic basis of EE, with the majority due to monogenic causes. Monogenic etiologies of EE include pathogenic variants in the γ‐aminobutyric acid type A receptor (GABA‐A) encoding gene family. We present a 2‐year‐old patient with EE, hypotonia, and global developmental delays. Clinical trio exome sequencing showed a novel, de novo variant in GABRG1. GABRG1 encodes the γ1 subunit of the GABA‐A receptor. To date, there has not been an association of EE with pathogenic variants in GABRG1. This variant is predicted to be damaging to protein structure and function, and the patient's phenotype is similar to those with pathogenic variants in other members of the GABA‐A receptor encoding gene family.

GABRG1 variant as a potential novel cause of epileptic encephalopathy, hypotonia, and global developmental delay

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Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management

GABRG1 variant as a potential novel cause of epileptic encephalopathy, hypotonia, and global developmental delay