Genetic evaluation of five patients with ROHHAD-NET using whole genome sequencing and optical genome mapping

Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation (ROHHAD) and neuroendocrine tumor (NET) is a very rare condition with an unknown etiology. While various potential causes have been hypothesized, including genetic and paraneoplastic autoimmune mechanisms, no definitive cause has been identified to date. This study aimed to explore whether patients with ROHHAD-NET share an underlying heritable genetic etiology.

We identified five female patients clinically suspected of having ROHHAD(-NET); among them in two patients a NET was found: a ganglioneuroma and a low grade cerebellar ganglion cell tumor with BRAF mutation. To identify potential pathogenic germline genomic variants, whole genome sequencing (WGS) was performed on germline DNA from all five patients, including four patient-parent trios. Furthermore, optical genome mapping (OGM) was performed for two patients to detect germline structural variants (SVs). Rare single nucleotide variants (SNVs) and small insertions/deletions (InDels) were identified through WGS and rare SVs affecting (non)-coding or regulatory regions were analyzed using both WGS and OGM. We explored a de novo, inherited autosomal dominant and autosomal recessive inheritance scenario. However, no candidate variants in a recurrently affected gene locus or genomic region were identified in two or more patients.

Our comprehensive genome-wide data analysis did not reveal evidence of a monogenetic cause for ROHHAD-NET. Whereas these findings do not exclude a genetic etiology for ROHHAD-NET, they strengthen the hypothesis of an autoimmune origin for symptoms of ROHHAD.