PracticeUpdate Conference Series - SSIEM 2018

Whole Exome Sequencing Is a Potent First-Line Diagnostic Tool for NeurometabolicDisorders Covering a wide phenotypic spectrum, whole exome sequencing facilitates a definite diagnosis in 46% and possible diagnosis in 30% of cases. W hole exome sequencing has been demonstrated to be a potent first-line diagnostic tool (approximately 50%; >3000) are expected to be uncovered in the next decade.

Dr. Buchert explained that molecular diagnoses of inherited neurometabolic disorders are challenging due to genetic and clinical heterogeneity. Especially in inborn errors of metabolism, early identification is crucial for treatment decisions. Neurometabolic disorders are a subgroup of inborn errors of metabolism with neurological manifestations. They are the largest group of genetic intellectual developmental disorders amenable to causal therapy targeting pathophysiology, such as medical diets, supplements, medications, hematopoietic stem cell transplants, and gene therapy. Early diagnosis is critical for timely initiation of treatment and prevention of irreversible brain damage. Traditional observational epidemiology is inefficient in elucidating rare and clinically and genetically heterogeneous Mendelian diseases such as neurometabolic disorders. Despite extensive, expensive, and often invasive testing, diagnostic delays are common and many patients remain undiagnosed. These concerning challenges have begun to be addressed with the advent of genome-wide screening approaches based on next- generation sequencing (NGS). An alternative to whole genome sequencing is sequencing a portion of the genome, either the entire set of protein-coding sequences (whole exome sequencing) or a subset (gene panels). Due to its lower cost, the whole exome sequencing has been used widely to identify the genetic basis of rare Mendelian disorders. Whole exome sequencing has skyrocketed the pace at which new gene-disease associations are established. With further advances in NGS, the majority of unknown gene-disease associations

In addition, NGS has facilitated detection of new gene-phenotype associations for genes that have been implicated in Mendelian conditions either by establishing causative relationships with different known or novel conditions or by expanding the clinical spectrum of established Mendelian conditions. These new discoveries of rare diseases genetics enhance the ability to diagnose patients. In 2016, the diagnostic efficiency of exome- wide and large gene panel sequencing in children with complex neurometabolic phenotypes was established. This success further supported the assertion that next-generation sequencing + exquisite data interpretation is the most time-efficient path to definite diagnosis in these rare heterogeneous conditions. Given the limitations of the exome- sequencing technology combined with slow updating of included genes within DNA capture technologies, the more promising approach is an up-to-date virtual panel of known disease genes applied to whole genome sequencing data. This combination allows clinical restriction to a subset of genetic information, but allows future exploration of the entire genome for undiagnosed cases. Though NGS-based genetic testing is established in Europe, researchers and clinicians need to promote the potential benefit of whole exome/genome sequencing as a first-line diagnostic tool. Dr. Buchert concluded that whole exome sequencing is a potent first-line diagnostic tool for neurometabolic disorders. Though the phenotypic spectrum is wide and variable, whole exome sequencing facilitated a definite diagnosis in 46% and a possible diagnosis pending follow-up in 30% of cases.

for neurometabolic disorders. Amid a wide phenotypic spectrum, whole exome sequencing facilitated a definite diagnosis in 46% and possible diagnosis pending follow-up in 30% of cases, reports a whole exome sequencing evaluation. Rebecca Buchert, MD, of the University of Tuebingen in Germany, reported results of whole exome sequencing-based diagnostics in a cohort of 97 index cases to evaluate the diagnostic utility of such sequencing in inherited neurometabolic disorders. Inclusion criteria were suspected neurometabolic disorders based on biochemical or radiological findings. Coding genomic regions were enriched for sequencing as 2×125 bp/2×100 bp paired-end reads on an Illumina HiSeq2500/NovaSeq6000 system. Generated sequences were analyzed using the megSAP pipeline. Clinical variant prioritization included filtering steps according to an in-house operating procedure. In 44 (46%) cases, likely pathogenic or pathogenic variants were identified in genes associated with neurometabolic disorders (n=135) or other neurodevelop- mental disorders (n=9). Targeted therapy was available in 36% of these. In 33%, established diagnoses implicated a modification of clinical management. In 31% of cases, however, disorders were not amenable to targeted therapy. In 29 cases (30%) variants of unknown significance were identified with pending follow-up studies for functional analyses. Moreover, five candidate genes were newly identified. A total of 18 cases (19%), however, remain unsolved. Ongoing investigations of the latter in a research setting include whole genome and transcriptome sequencing.

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SSIEM 2018 • PRACTICEUPDATE CONFERENCE SERIES 15