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A respiratory/Hirschsprung phenotype in a three-generation family associated with a novel pathogenic PHOX2B splice donor mutation.
Mol Genet Genomic Med. 2020 12; 8(12):e1528.MG

Abstract

BACKGROUND

Mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non-REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non-PARM missense, nonsense or frameshift mutations.

METHODS

We describe a three-generation Maltese-Caucasian family with a variable respiratory/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non-invasive ventilation.

RESULTS

The sequencing of PHOX2B revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS/Hirschsprung phenotype in the family. The mutation generates a non-functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria.

CONCLUSION

This report is significant as no PHOX2B splice-site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non-PARM mutations.

Links

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Authors+Show Affiliations

Pace NP
Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
Pace Bardon M
Department of Medicine, Mater Dei Hospital, Msida, Malta.
Borg I
Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, Malta. Medical Genetics Unit, Department of Pathology, Mater Dei Hospital, Msida, Malta. Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.

MeSH

AdultFemaleHirschsprung DiseaseHomeodomain ProteinsHumansHypoventilationInfantLoss of Function MutationMaleMiddle AgedPedigreePhenotypeProtein DomainsRNA SplicingSleep Apnea, CentralTranscription Factors

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

33047879

Citation

Pace, Nikolai Paul, et al. "A respiratory/Hirschsprung Phenotype in a Three-generation Family Associated With a Novel Pathogenic PHOX2B Splice Donor Mutation." Molecular Genetics & Genomic Medicine, vol. 8, no. 12, 2020, pp. e1528.
Pace NP, Pace Bardon M, Borg I. A respiratory/Hirschsprung phenotype in a three-generation family associated with a novel pathogenic PHOX2B splice donor mutation. Mol Genet Genomic Med. 2020;8(12):e1528.
Pace, N. P., Pace Bardon, M., & Borg, I. (2020). A respiratory/Hirschsprung phenotype in a three-generation family associated with a novel pathogenic PHOX2B splice donor mutation. Molecular Genetics & Genomic Medicine, 8(12), e1528. https://doi.org/10.1002/mgg3.1528
Pace NP, Pace Bardon M, Borg I. A respiratory/Hirschsprung Phenotype in a Three-generation Family Associated With a Novel Pathogenic PHOX2B Splice Donor Mutation. Mol Genet Genomic Med. 2020;8(12):e1528. PubMed PMID: 33047879.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A respiratory/Hirschsprung phenotype in a three-generation family associated with a novel pathogenic PHOX2B splice donor mutation. AU - Pace,Nikolai Paul, AU - Pace Bardon,Michael, AU - Borg,Isabella, Y1 - 2020/10/13/ PY - 2020/06/21/received PY - 2020/08/22/revised PY - 2020/09/25/accepted PY - 2020/10/14/pubmed PY - 2021/6/23/medline PY - 2020/10/13/entrez KW - Congenital Central Hypoventilation Syndrome KW - Hirschsprung disease KW - PHOX2B gene SP - e1528 EP - e1528 JF - Molecular genetics & genomic medicine JO - Mol Genet Genomic Med VL - 8 IS - 12 N2 - BACKGROUND: Mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non-REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non-PARM missense, nonsense or frameshift mutations. METHODS: We describe a three-generation Maltese-Caucasian family with a variable respiratory/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non-invasive ventilation. RESULTS: The sequencing of PHOX2B revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS/Hirschsprung phenotype in the family. The mutation generates a non-functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria. CONCLUSION: This report is significant as no PHOX2B splice-site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non-PARM mutations. SN - 2324-9269 UR - https://www.unboundmedicine.com/medline/citation/33047879/A_respiratory/Hirschsprung_phenotype_in_a_three_generation_family_associated_with_a_novel_pathogenic_PHOX2B_splice_donor_mutation_ DB - PRIME DP - Unbound Medicine ER -