Purpose: The rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome has diverse clinical features such as morbid obesity, hypothalamic/pituitary dysfunction, and behavioral or developmental disorders. Although several candidate genes have been suggested, a possible genetic basis for ROHHAD syndrome remains unknown. This study was performed to describe clinical and endocrine characteristics of patients with ROHHAD syndrome and to identify genetic etiology using whole exome sequencing (WES). Patients and methods: This study included 3 probands (two males and a female) and their parents. Clinical and biochemical features were reviewed retrospectively. Enrichment of coding exons and flanking intronic regions was performed with TruSeq Exome Enrichment Kit (Illumina Inc., San Diego, CA, USA). WES was performed using HiSeq2000 platform (Illumina Inc.). Reads were aligned to the reference genome using the BWA program and the aligned reads were processed using SAM tools. Variant calling was performed by the Genome Analysis Tool Kit. Results: Subject 1 manifested rapid-onset obesity at age 3 years and presented with acute renal failure and combined pituitary hormone deficiency (CPHD) at age 5 years. She was admitted because of central hypoventilation. She is currently 20 years old and her body mass index is ＞97th percentile (27.6 kg/m2). No mutations were identified in PHOX2B and POMC by Sanger sequencing. Subject 2, a 10-year-old female, manifested rapid-onset obesity at age 2.5 years. She was brought to the hospital due to central hypoventilation requiring tracheostomy and diagnosed with CPHD at age 6.1 years. Subject 3 is an 18-year-old male who presented with esophageal varix bleeding, liver cirrhosis, obesity, and type 2 diabetes mellitus at age 13 years. He had central hypothyroidism, growth hormone deficiency, and hypogonadotropic hypogonadism. WES identified a novel heterozygous variant of c.8747G＞A (p.R2916H) in LRP1, which regulates leptin signaling. The other patients did not harbor pathogenic or likely pathogenic sequence variants. Conclusions: ROHHAD syndrome should be considered in patients with morbid obesity and CPHD. Further study is needed to investigate long-term outcomes on respiratory failure, neuroendocrine tumors, and mortality and to identify molecular basis of ROHHAD syndrome.