Whole genome sequencing in ROHHAD trios proved inconclusive: what's beyond?

Area of Science:

• Pediatric rare diseases
• Genetics and Genomics
• Neuroendocrinology

Background:

• Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a rare, life-threatening pediatric disorder.
• Diagnosis is challenging due to poorly understood clinical manifestations and lack of confirmatory tests.
• ROHHAD is characterized by rapid weight gain, hypothalamic and autonomic dysfunction, and hypoventilation.

Purpose of the Study:

• To investigate potential genetic risk factors for ROHHAD by analyzing non-coding variants.
• To identify shared genetic changes in pediatric ROHHAD trios.

Main Methods:

• Analysis of non-coding variants (SNVs, indels, splice variants, copy number variations) in two ROHHAD trios (proband with parents).
• Recruitment of patients from Gaslini Children's Hospital, Genoa, Italy.
• Search for shared gene variants or altered genomic regions between the two probands.

Main Results:

• No potentially pathogenic genetic changes, involving shared genes, regions, or pathways, were identified between the two ROHHAD trios.
• The findings are consistent with the clinical phenotype of ROHHAD.

Conclusions:

• The current analysis did not reveal shared genetic etiology for ROHHAD in the studied trios.
• Further investigation using advanced sequencing technologies (long-read sequencing, optical mapping) and multi-omic datasets (immunological, autoimmune) is recommended to explore other potential causes.