Amy Zhou1, Casey M Rand1, Sara M Hockney1,2, Grace Niewijk1, Patrick Reineke3, Virginia Speare3, Elizabeth M Berry-Kravis4, Lili Zhou4, Lawrence J Jennings5,6, Min Yu5, Isabella Ceccherini7, Tiziana Bachetti7,8, Melanie Pennock9, Kai Lee Yap5,6, Debra E Weese-Mayer10,11,12. 1. Department of Pediatrics, Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, IL, USA. 2. Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 3. Ambry Genetics, Aliso Viejo, CA, USA. 4. Departments of Pediatrics, Neurology, and Biochemistry, Molecular Diagnostics Laboratory, Rush University Medical Center, Chicago, IL, USA. 5. Department of Pathology, Molecular Diagnostics Laboratory, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA. 6. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. 7. IRCCS Istituto Giannina Gaslini, Genoa, Italy. 8. Lab Neurobiologia dello Sviluppo, Dip. Scienze della Terra dell'Ambiente e della Vita (DISTAV), Università di Genova, Genova, Italy. 9. North Bristol NHS Trust, Bristol, UK. 10. Department of Pediatrics, Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital of Chicago and Stanley Manne Children's Research Institute, Chicago, IL, USA. D-Weese-Mayer@Northwestern.edu. 11. Northwestern University Feinberg School of Medicine, Chicago, IL, USA. D-Weese-Mayer@Northwestern.edu. 12. Department of Pediatrics, Pediatric Autonomic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. D-Weese-Mayer@Northwestern.edu.
Abstract
PURPOSE: CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype-phenotype correlations that will guide anticipatory management. METHODS: An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher's exact test; further pairwise comparisons were made on significant results. RESULTS: Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function. CONCLUSION: This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype-phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.
PURPOSE: CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype-phenotype correlations that will guide anticipatory management. METHODS: An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher's exact test; further pairwise comparisons were made on significant results. RESULTS: Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function. CONCLUSION: This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype-phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.