Causative and common PHOX2B variants define a broad phenotypic spectrum

Abstract

Paired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collec-

Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS)

“…Trasmission of CCHS is autosomal dominant with variable expressivity and incomplete penetrance, and without any gender preference (Weese-Mayer et al, 2003;Bachetti and Ceccherini, 2020). Variable CCHS-like phenotypes have been reported associated with whole and partial gene deletions of PHOX2B as extensively reported (Jennings et al, 2012;Bachetti and Ceccherini, 2020).…”

“…The variable phenotypes reported in CCHS patients carrying the same mutation also suggest the involvement of modifier genes of expressivity (Di Lascio et al, 2018a;Bachetti and Ceccherini, 2020). Mutations in genes other than PHOX2B, involved in the differentiation of neural crest cells (RET, GDNF, BDNF, GFRA1, PHOX2A, HASH-1, EDN1, EDN3, BMP2) or in oncogenes (BRAF) (Bolk et al, 1996;Amiel et al, 1998;Weese-Mayer et al, 2002Sasaki et al, 2003;Fernández et al, 2013;Al Dakhoul, 2017) have been found in some CCHS individuals.…”

“…The age of presentation of CCHS is typically in newborns, but it may also be diagnosed later in childhood or adulthood [lateronset (LO) CCHS] (Weese- Mayer et al, 2005;Antic et al, 2006;Trochet et al, 2008b;Basu et al, 2017). The disease can be isolated (Di Lascio et al, 2018b;Bachetti and Ceccherini, 2020), or associated with a spectrum of non-respiratory symptoms, among which seizures (Binmanee et al, 2020) and other conditions that reflect a more global ANS dysfuntion, including cardiac arrhythmias and congenital heart disease (Lombardo et al, 2018;Laifman et al, 2020), ocular disorders, the aganglionic megacolon Hirschsprung's disease and neural crest tumors (reviewed in Di Lascio et al, 2018a,b;Broch et al, 2019;Bachetti and Ceccherini, 2020;Trang et al, 2020).…”

Guidelines for diagnosis and management of congenital central hypoventilation syndrome

“…Familial cases with CCHS exist [ 22 , 45 , 46 , 48 , 53 , 86 , 95 ], due to parental transmission of somatic and germline mosaic mutations [ 6 , 9 , 72 ]. In the meantime, PHOX2B -mediated mechanisms have been extensively investigated and better understood in vitro [ 4 , 5 , 7 , 8 , 20 , 24 , 25 , 68 , 97 ], in vivo [ 27 , 44 , 70 ], and in CCHS patients [ 28 , 33 , 92 – 94 , 99 ]. However, most pathogenic pathways are yet to be disclosed.…”

The past and future of genetics in pulmonary disease: You can teach an old dog new tricks

“…Whole‐exome sequencing, which covers the 1% to 2% of the genome that encodes proteins, is somewhat a misnomer, as it does not completely cover the entire exome, and different methodologies may have different gaps. Whole‐exome sequencing will also not identify small repeat expansions, such as in PHOX2B (congenital central hypoventilation 13 ). Probably more important, current clinical, or medical whole‐exome studies generally only report variants in the ~20% of genes known to be associated with the disease.…”