Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype–phenotype correlation in congenital central hypoventilation syndrome (CCHS)

Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype–phenotype correlation in congenital central hypoventilation syndrome (CCHS)

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 anticipa...

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Published in:Genetics in medicine Vol. 23; no. 9; pp. 1656 - 1663
Main Authors: Zhou, Amy, Rand, Casey M., Hockney, Sara M., Niewijk, Grace, Reineke, Patrick, Speare, Virginia, Berry-Kravis, Elizabeth M., Zhou, Lili, Jennings, Lawrence J., Yu, Min, Ceccherini, Isabella, Bachetti, Tiziana, Pennock, Melanie, Yap, Kai Lee, Weese-Mayer, Debra E.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01-09-2021
Elsevier Limited
Subjects:
Authorship
Biomedical and Life Sciences
Biomedicine
Collaboration
Congenital diseases
Genes, Homeobox
Genetic Association Studies
Genetics
Genotype & phenotype
Homeodomain Proteins - genetics
Hospitals
Human Genetics
Humans
Hypoventilation
Hypoventilation - congenital
Laboratories
Laboratory Medicine
Medicine
Mutation
Pathology
Patients
Pediatrics
Proteins
Sleep Apnea, Central
Tumors
Ventilation
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Summary: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.
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ISSN:1098-3600
1530-0366
DOI:10.1038/s41436-021-01178-x