Whole exome sequencing identifies RAI1 mutation in a morbidly obese child diagnosed with ROHHAD syndrome

Abstract

Context: The current obesity epidemic is attributed to complex interactions between genetic and environmental factors. However, a limited number of cases, especially those with early-onset severe obesity, are linked to single gene defects. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is one of the syndromes that presents with abrupt-onset extreme weight gain with an unknown genetic basis.

Objective: To identify the underlying genetic etiology in a child with morbid early-onset obesity, hypoventilation, and autonomic and behavioral disturbances who was clinically diagnosed with ROHHAD syndrome. Design/Setting/Intervention: The index patient was evaluated at an academic medical center. Whole-exome sequencing was performed on the proband and his parents. Genetic variants were validated by Sanger sequencing.

Results: We identified a novel de novo nonsense mutation, c.3265 C>T (p.R1089X), in the retinoic acid-induced 1 (RAI1) gene in the proband. Mutations in the RAI1 gene are known to cause Smith-Magenis syndrome (SMS). On further evaluation, his clinical features were not typical of either SMS or ROHHAD syndrome.

Conclusions: This study identifies a de novo RAI1 mutation in a child with morbid obesity and a clinical diagnosis of ROHHAD syndrome. Although extreme early-onset obesity, autonomic disturbances, and hypoventilation are present in ROHHAD, several of the clinical findings are consistent with SMS. This case highlights the challenges in the diagnosis of ROHHAD syndrome and its potential overlap with SMS. We also propose RAI1 as a candidate gene for children with morbid obesity.

Figures

Figure 1.

Phenotypic, anthropometric, and genetic findings in the proband. A, Pedigree of the family; the proband is II:1. B–E, Physical findings of the proband. B, Facial features of the proband as an infant (left) with the unaffected sister (right). C and D, Facial features of the proband at 11 years—front (C) and side view (D). E, Image of the hands, showing small hands. F and G, Anthropometric measurements. F, Height and weight trajectory on the CDC 2000 growth curves. G, BMI curves for age. H, Sanger DNA sequencing of genomic PCR products showing the de novo c.3265C>T mutation (noted with asterisk) in the proband, absent in both parents and unaffected sibling.