Abstract
BackgroundRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.MethodsWe sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.ResultsThe analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.ConclusionsClinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0314-x) contains supplementary material, which is available to authorized users.
Highlights
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified
Cohort characteristics A total of 35 ROHHAD patients in whom the clinical diagnosis was confirmed were included in this cohort for genetic investigation (Table 1)
7 of these patients were included in the initial, trio-based, exome sequencing analysis, while 28 other ROHHAD patients were included in the secondary exome and Sanger sequencing analysis
Summary
Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a complex and devastating disease whose etiology is poorly understood, despite its initial description 50 years ago [1]. In addition to the hypothalamic, respiratory and autonomic manifestations that are hallmarks of the disease, about 40 % of ROHHAD patients develop benign tumours of neural crest origin [2,3,4]. Due to the variable timing and onset of other features, coupled with the presumption of exogenous obesity, a ROHHAD diagnosis is often delayed or missed, potentially leading to fatal central hypoventilation, cardiorespiratory arrest, and impaired neurocognitive development. The identification of a diagnostic marker (genetic or otherwise) has the potential to decrease morbidity and mortality of patients with ROHHAD, and to guide future intervention and research on this disease
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