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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):... PurposeCCHS 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.MethodsAn 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.ResultsThree 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.ConclusionThis 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Genetics in Medicine Springer Journals

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

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References (36)

Publisher
Springer Journals
Copyright
Copyright © The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics 2021
ISSN
1098-3600
eISSN
1530-0366
DOI
10.1038/s41436-021-01178-x
Publisher site
See Article on Publisher Site

Abstract

PurposeCCHS 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.MethodsAn 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.ResultsThree 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.ConclusionThis 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.

Journal

Genetics in Medicine – Springer Journals

Published: Sep 1, 2021

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