Genetic analysis of a European cohort of ROHHAD patients

Federica Buonocore; Manuela Cerbone; Tony Brooks; Shaikh M Guftar; Emmeline Heffernan; Raúl Montero; Sonya Galcheva; Violeta Iotova; Zainaba Mohamed; Flavia Napoli; John Anderson; Mohamad Maghnie; Dattani Mehul T.

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ESPE Abstracts (2024) 98 P1-185

ESPE2024 Poster Category 1 Pituitary, Neuroendocrinology and Puberty 3 (9 abstracts)

Genetic analysis of a European cohort of ROHHAD patients

Federica Buonocore ¹ , Manuela Cerbone ^1,2 , Tony Brooks ³ , M Guftar Shaikh ⁴ , Emmeline Heffernan ⁵ , Raúl Montero ⁶ , Sonya Galcheva ⁷ , Violeta Iotova ⁸ , Zainaba Mohamed ⁹ , Flavia Napoli ¹⁰ , John Anderson ¹¹ , Mohamad Maghnie ^10,12 & Mehul T. Dattani ^1,2

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¹Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. ²Department of Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. ³UCL Genomics, UCL Zayed Centre for Research into Rare Disease in Children, London, United Kingdom. ⁴Department of Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom. ⁵Royal Belfast Hospital for Sick Children, Belfast, United Kingdom. ⁶Pediatric intensive Care Unit Reina sofia Hospital, Cordoba, Spain. ⁷Department of Paediatrics, Varna Medical University/University Hospital "St. Marina", Varna, Bulgaria. ⁸Department of Pediatrics, Medical University of Varna, Varna, Bulgaria. ⁹Department of Endocrinology, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom. ¹⁰Pediatric Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy. ¹¹Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. ¹²D.I.N.O.G.M.I., Università degli studi di Genova, Genova, Italy

Introduction: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare life-limiting paediatric condition, with about 200 reported cases worldwide. The disease typically presents in early childhood (1.5-5y) with rapid-onset obesity. Other clinical symptoms may include central hypoventilation, hypothalamo-pituitary (H-P) dysfunction (hyperprolactinaemia, salt-water imbalances, anterior pituitary deficits) and autonomic dysregulation, contributing to the severity of the phenotype. Approximately 40-50% of patients develop neural crest tumours (ROHHADNET), which can arise within two years of initial weight gain. The aetiology remains unknown, and diagnosis currently relies on the clinical features only. These tend to unfold overtime, hence the diagnosis is often delayed or missed. No genetic variants have been identified to date and no specific treatment is available.

Aims and Methods: We aimed to investigate the molecular basis of ROHHAD syndrome, using next generation sequencing (NGS) technologies. Our cohort includes 13 patients (males, n = 7; females, n = 6) followed up at Great Ormond Street Hospital (London, UK) and other national/international centres (Scotland, Northern Ireland, Spain, Bulgaria). We have collected DNA from the patient and both parents, and carried out whole genome sequencing (WGS; n = 10) or exome sequencing (WES; n = 3).

Results: Overall, an average of 45X coverage of the target genome was achieved, indicating adequate coverage for variant calling. Single nucleotide variants (SNVs), copy number variants (CNVs) and structural variants (SVs) were analysed in each family trio using an unbiased approach. Pathogenic or likely pathogenic variants that were shared among all ROHHADNET patients were also considered. Variant prioritisation analyses included de novo, autosomal recessive homozygous and compound heterozygous, and dominant mode of inheritance. Genes that have been previously associated with H-P development and related disorders were also screened. Preliminary data suggest that a simple mendelian inheritance is to be excluded, with the likely involvement of more than one gene. Identified potentially pathogenic filtered variants are currently under investigation.

Conclusion: Despite its clinical significance, the underlying molecular mechanisms of ROHHADNET syndrome remain unknown. Given the highly variable clinical phenotypes, an oligogenic causative mechanism as well as an epigenetic basis need to be considered. WGS/WES represent valuable methodologies for the discovery of novel candidate genes that would uncover new genetic disease mechanisms. Defining the specific aetiology will also have important consequences for both patients and their parents for an earlier diagnosis and clinical intervention with improved patient management, genetic counselling for families and, ultimately, developing targeted therapies for this life-threatening condition.