Exome Sequencing and the Management of Neurometabolic Disorders

Abstract

BACKGROUND Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…Since 2010, genetic analyses based on so-called next-generation sequencing (NGS), such as wholeexome sequencing (WES) (20)(21)(22)(180)(181)(182), have gradually entered medical practice, especially in the past five years. WES allows the simultaneous sequencing of nearly 20 000 genes (20)(21)(22)180).…”

“…Over the past nearly five years, genetic assessment of patients with inherited diseases, including CHH/KS, has increasingly used massively parallel next-generation sequencing (NGS), allowing simultaneous analysis of tens to thousands of genes, depending on whether targeted-exome or whole-exome sequencing is used (2,(20)(21)(22). Consequently, detecting more than one rare but potentially deleterious variants in a given patient (oligogenism or potential oligogenism) is becoming increasingly common (20)(21)(22).…”

“…Consequently, detecting more than one rare but potentially deleterious variants in a given patient (oligogenism or potential oligogenism) is becoming increasingly common (20)(21)(22). This review summarizes the classical modes of transmission for CHH/KS loci reported in the literature, and explores the growing role of oligogenism.…”

MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature

“…Several novel genes involved in overgrowth conditions were recently identified through WES (Supplementary Table 2) (69, 70, 71). WES was proved to be a useful and powerful tool to establish the diagnosis of complex conditions (72,73). In the years to come, with increased access to these techniques, it is possible to expect an improvement in the establishment of the diagnosis of overgrowth patients.…”

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

“…The products were sequenced on the Illumina HiSeq 2500 with v.4 chemistry. A customized bioinformatics pipeline, 11 coupled with visual validation (Integrative Genomics Viewer), identified variants of interest. Individual 3 underwent trio-based Illumina exome sequencing at GeneDx, a diagnostic laboratory certified by the College of American Pathologists and Clinical Laboratory Improvement Amendments.…”