Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours

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.

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…The absence of PHOX2B mutations in individuals with ROHHAD, despite its clinical similarity to CCHS, suggests that other genes or regulatory sequences may be associated with autonomic function and NB pathogenesis (89).…”

Rapid onset obesity and ondine’s curse: a deadly syndrome

“…16 It was later confirmed that none of these 8 genes or RAI1 gene were major ROHHAD genes. 17 In our case, none of the tested genes were positive. A negative test could be due to variation in the genomic region not covered by the test; or due to large insertions, deletions, duplications, inversions, complex rearrangements which cannot be detected.…”

“…Use of patients' neuroendocrine tumour represents one approach to address this challenge. 17 Hence unambiguous identification of ROHHAD syndrome has been challenging; confirmatory laboratory testing is not yet available, and the patient population may represent heterogeneous group of underlying etiologies. Hence emphasis on diagnosis based on clinical findings.…”

Perioperative anesthetic management of children with congenital central hypoventilation syndrome and rapid‐onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation undergoing thoracoscopic phrenic nerve‐diaphragm pacemaker implantation

“…Less severe phenotypes associated with PARMs such as 20/24 and a subset of 20/25 cases, may lead to a delayed diagnosis until later in childhood or in adulthood, when this condition may be unmasked after pneumonia or administration of sedatives or anesthetics . ROHHAD typically presents in early childhood (1.5‐7 years old) with rapid weight gain of 20‐30 pounds over a 3‐6 month period, and a phenotype that “unfolds” over time including severe alveolar hypoventilation; it has no identified genetic basis at present, despite aggressive inquiry . In both patient populations, surgically implanted diaphragmatic pacemakers decrease the need for constant mechanical ventilation by stimulating the phrenic nerve to ensure regular breathing for up to 12‐15 hours per day …”

“…1 ROHHAD typically presents in early childhood (1.5-7 years old) with rapid weight gain of 20-30 pounds over a 3-6 month period, and a phenotype that "unfolds" over time including severe alveolar hypoventilation; it has no identified genetic basis at present, despite aggressive inquiry. [5][6][7] In both patient populations, surgically implanted diaphragmatic pacemakers decrease the need for constant mechanical ventilation by stimulating the phrenic nerve to ensure regular breathing for up to 12-15 hours per day. 8,9 Phrenic nerve-diaphragm pacemakers can be life-changing for patients who require continuous artificial ventilation, allowing them to lead physically active lives with exertion in moderation without being tethered to a ventilator during the day (Figure 1).…”