CCHS PHOX2B

A rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system. The incidence is estimated to be at 1 of 200 000 livebirths. A heterozygous mutation of PHOX-2B gene is found in 90% of the patients. Association with a Hirschsprung's disease is observed in 16% of the cases (adapted from Mondo)¹.

Prevalence

Incidence is 1:148000-200000 births (Estimated, may include mild/undiagnosed or be overestimated globally)². Rare, but reported worldwide³.

Age of Onset Details

Typical: 0-2^2,3; Range: 0-36⁴.

Locus

hg19

chr4:41747989-41748049

hg38

chr4:41745972-41746032

t2t

chr4:41719745-41719805

Details

Alleles of 24 repeats (and sometimes 25 repeats) correspond to delayed disease onset and/or milder phenotype; alleles above benign range (9-20 repeats) and below the pathogenic range (26-33 repeats) have uncertain significance².

Mechanism

LoF/GoF

Polyalanine expansion leading to loss or gain of function, dependent on altered protein product^5,2. Correlation between length and reduced transcriptional activity⁶.

Year

2003⁷

Location in Gene

Exon 3

Gene Strand

Alleles

Ref. Motif

GCN

Pathogenic (ref.)

GCN

Pathogenic (gene)

CNG

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0800026

Congenital Central Hypoventilation Syndrome

Debra E.,Weese-Mayer, Casey M.,Rand, Ilya,Khaytin, Susan M.,Slattery, Kai Lee,Yap, Mary L.,Marazita, Elizabeth M.,Berry-Kravis

GeneReviews® · 1993-01-01

genereviews:NBK1427

PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome.

I,Matera, T,Bachetti, F,Puppo, M,Di Duca, F,Morandi, G M,Casiraghi, M R,Cilio, R,Hennekam, R,Hofstra, J G,Schöber, R,Ravazzolo, G,Ottonello, I,Ceccherini

Journal of medical genetics · 2004-05-01

pmid:15121777

PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.

Nick A,Antic, Beth A,Malow, Neale,Lange, R Doug,McEvoy, Amy L,Olson, Peter,Turkington, Wolfram,Windisch, Martin,Samuels, Cathy A,Stevens, Elizabeth M,Berry-Kravis, Debra E,Weese-Mayer

American journal of respiratory and critical care medicine · 2006-07-27

pmid:16873766

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome.

Tiziana,Bachetti, Ivana,Matera, Silvia,Borghini, Marco,Di Duca, Roberto,Ravazzolo, Isabella,Ceccherini

Human molecular genetics · 2005-05-11

pmid:15888479

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Jeanne,Amiel, Béatrice,Laudier, Tania,Attié-Bitach, Ha,Trang, Loïc,de Pontual, Blanca,Gener, Delphine,Trochet, Heather,Etchevers, Pierre,Ray, Michel,Simonneau, Michel,Vekemans, Arnold,Munnich, Claude,Gaultier, Stanislas,Lyonnet

Nature genetics · 2003-03-17

pmid:12640453

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Recurrence of CCHS-associated PHOX2B Poly-Alanine expansion variant due to paternal mosaicism.

Huling,Jiang, Zepeng,Ping, Suping,Li, Jianjun,Zhu

Gene · 2024-03-11

pmid:38467313

Pulmonary hypertension in an adult patient with congenital central hypoventilation syndrome: a case report.

Yosuke,Terui, Shoko,Ohura, Tetsuji,Nozaki, Takuya,Yagi

European heart journal. Case reports · 2024-02-26

pmid:38454954

Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.

Rosa,Antón, Miguel Á,Treviño, David,Pantoja-Uceda, Sara,Félix, María,Babu, Eurico J,Cabrita, Markus,Zweckstetter, Philip,Tinnefeld, Andrés M,Vera, Javier,Oroz

Nature communications · 2024-03-02

pmid:38431667

Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.

E E,Evers-Bikker, W,de Weerd, P J,Wijkstra, L,Corel, L P,Verweij, B A H,Vosse

European journal of pediatrics · 2023-11-25

pmid:38001308

Caroline B,Ferreira, Talita M,Silva, Phelipe E,Silva, Claudio L,Castro, Catherine,Czeisler, José J,Otero, Ana C,Takakura, Thiago S,Moreira

eLife · 2022-11-17

pmid:36394266

Generation of two hiPSC lines (UMILi027-A and UMILi028-A) from early and late-onset Congenital Central hypoventilation Syndrome (CCHS) patients carrying a polyalanine expansion mutation in the PHOX2B gene.

Ana Lucia,Cuadros Gamboa, Roberta,Benfante, Monica,Nizzardo, Tiziana,Bachetti, Paride,Pelucchi, Valentina,Melzi, Cinzia,Arzilli, Marta,Peruzzi, Rolland A,Reinbold, Silvia,Cardani, Amelia,Morrone, Renzo,Guerrini, Ileana,Zucchi, Stefania,Corti, Isabella,Ceccherini, Raffaele,Piumelli, Niccolò,Nassi, Simona,Di Lascio, Diego,Fornasari

Stem cell research · 2022-04-07

pmid:35421844

Genetic study of a patient with congenital central hypoventilation syndrome in Iran: a case report.

Reihaneh,Khorasanian, Marzieh,Mojbafan, Nastaran,Khosravi

Molecular biology reports · 2021-10-09

pmid:34626313

Congenital central hypoventilation syndrome in neonates: report of fourteen new cases and a review of the literature.

Mei,Mei, Lin,Yang, Yulan,Lu, Laishuan,Wang, Guoqiang,Cheng, Yun,Cao, Chao,Chen, Liling,Qian, Wenhao,Zhou

Translational pediatrics · 2021-04-01

pmid:34012823

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

Amy,Zhou, Casey M,Rand, Sara M,Hockney, Grace,Niewijk, Patrick,Reineke, Virginia,Speare, Elizabeth M,Berry-Kravis, Lili,Zhou, Lawrence J,Jennings, Min,Yu, Isabella,Ceccherini, Tiziana,Bachetti, Melanie,Pennock, Kai Lee,Yap, Debra E,Weese-Mayer

Genetics in medicine : official journal of the American College of Medical Genetics · 2021-05-06

pmid:33958749