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

Area of Science:

• Genetics
• Endocrinology
• Rare Diseases

Background:

• Rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neuroendocrine tumor (ROHHAD-NET) is a rare condition with an unknown cause.
• Hypotheses include genetic and paraneoplastic autoimmune mechanisms, but no definitive cause is identified.

Purpose of the Study:

• To investigate a potential underlying heritable genetic etiology in patients with ROHHAD-NET.

Main Methods:

• Whole genome sequencing (WGS) and optical genome mapping (OGM) were performed on five female patients and four patient-parent trios.
• Analysis focused on identifying rare single nucleotide variants, small insertions/deletions, and structural variants in coding, non-coding, and regulatory regions.
• Inheritance patterns including de novo, autosomal dominant, and autosomal recessive were explored.

Main Results:

• Five female patients with suspected ROHHAD(-NET) were identified; two had a neuroendocrine tumor (NET).
• No candidate variants in recurrently affected gene loci or genomic regions were found in multiple patients.
• Comprehensive genome-wide analysis did not reveal evidence of a monogenetic cause for ROHHAD-NET.

Conclusions:

• The study did not identify a monogenetic cause for ROHHAD-NET.
• These findings do not rule out a genetic etiology but strengthen the hypothesis of an autoimmune origin for ROHHAD symptoms.