Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation

Abstract

IMPORTANCE Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. OBJECTIVE To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation. DESIGN, SETTING, AND PARTICIPANTS Cohort study in which a total of 257 genes associated with monogenic neuroinflammation and/or cerebral vasculopathy, including monogenic noninflammatory diseases mimicking these entities, were selected. A customized enrichment capture array, the neuroinflammation gene panel (NIP), was created. Targeted high-coverage sequencing was applied to DNA samples taken from eligible patients referred to Great Ormond Street Hospital in London,

GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome

“…Similar to DARS-associated leukoencephalopathy, findings in GLRX5 associated neurological disorder might confuse neurologists toward diagnosing an acquired inflammatory disorder. The contrast enhancement noted in one patient also highlights the interesting association of mitochondria and inflammation as reported previously and has been highlighted in recent reports [ 21 , 22 ]. However, the persistent non-ketotic hyperglycinemia was an indication of a metabolic etiology.…”

GLRX5-associated [Fe-S] Cluster Biogenesis Disorder: Further Characterisation of the Neurological Phenotype and Long-term Outcome.

“…The contrast enhancement noted in one patient also highlights the interesting association of mitochondria and in ammation as reported previously and has been highlighted in recent reports. (21,22) However, the persistent non-ketotic hyperglycinemia was an indication of a metabolic etiology. It remains to be seen whether anti-in ammatory treatment with steroids has a disease modifying effect.…”

A case of Myhre syndrome mimicking juvenile scleroderma

“…This was a time consuming, costly, and mainly "clinician best guess" driven approach, which resulted in diagnostic delay of several months. Whole exome and genome sequencing and targeted gene panels now allow rapid, simultaneous detection of multiple genes, and are increasingly being used as diagnostic tools and to explore the pathogenesis of monogenic diseases [56][57][58][59][60][61]. These techniques are particularly useful for screening diseases with overlapping phenotypes.…”

“…These techniques are particularly useful for screening diseases with overlapping phenotypes. For instance, we (and many others) have used NGS to extensively study monogenic systemic inflammation, with significant diagnostic and therapeutic impact [ 60 , 61 ]. Similarly, we anticipate that application of NGS genetic screening to cohorts of patients with juvenile scleroderma (in all its forms) may identify a proportion with monogenic disease, and that evidence of tissue inflammation and autoimmunity should not preclude the possibility of a genetic diagnosis for the reasons discussed above.…”