A Common 3'UTR Variant of the PHOX2B Gene Is Associated With Infant Life-Threatening and Sudden Death Events in the Italian Population.

Tiziana Bachetti,Antonella Palmieri,Isabella Ceccherini,Simona Bagnasco,Raffaele Piumelli

doi:10.3389/fneur.2021.642735

Abstract

Heterozygous mutations in the Paired like homeobox 2b (PHOX2B) gene are causative of congenital central hypoventilation syndrome (CCHS), a rare monogenic disorder belonging to the family of neurocristopathies and due to a defective development of the autonomic nervous system. Most patients manifest sudden symptoms within 1 year of birth, mainly represented by central apnea and cyanosis episodes. The sudden appearance of hypoxic manifestations in CCHS and their occurrence during sleep resemble two other unexplained perinatal disorders, apparent life-threatening event (ALTE) and sudden and unexpected infant death (SUID), among which the vast majority is represented by sudden infant death syndrome (SIDS). Differently from CCHS, characterized by Mendelian autosomal dominant inheritance, ALTE and SIDS are complex traits, where common genetic variants, together with external factors, may exert an additive effect with symptoms likely manifesting only over a “threshold.” Given the similarities observed among the three abovementioned perinatal disorders, in this work, we have analyzed the frequency of PHOX2B common variants in two groups of Italian idiopathic ALTE (IALTE) and SUIDs/SIDS patients. Here, we report that the c*161G>A (rs114290493) SNP of the 3′UTR PHOX2B (i) became overrepresented in the two sets of patients compared to population matched healthy controls, and (ii) associated with decreased PHOX2B gene expression, likely mediated by miR-204, a microRNA already known to bind the 3′UTR of the PHOX2B gene. Overall, these results suggest that, at least in the Italian population, the SNP c*161G>A (rs114290493) does contribute, presumably in association with others mutations or polymorphisms, to confer susceptibility to sudden unexplained perinatal life-threatening or fatal disorders by increasing the effect of miR-204 in inducing PHOX2B expression down-regulation. However, these are preliminary observations that need to be confirmed on larger cohorts to achieve a clinical relevance.

Highlights

Paired like homeobox 2b (PHOX2B) gene acts in the early development of the autonomic nervous system (ANS), regulating the expression of downstream genes that lead to neuronal differentiation [1]
No causative variants were identified, we found common variants including a single-nucleotide polymorphism leading to synonymous changes c.552C>T; p.184Ser=(rs17885216) and an in-frame deletion of 7 alanine residues, shortening the 20 polyalanine (PolyAla) stretch to final 13 Ala residues, in PHOX2B
Our results confirmed the hypothesis that the c.∗161G>A SNP variant might play a role in PHOX2B gene expression regulation mediated by miR-204. Such an effect was not in contrast with results obtained without miR-204 given that IMR32 cells are characterized by very low miR-204 endogenous levels [30], likely not sufficient to disclose such an allele-specific effect. In this manuscript we have reported a PHOX2B variant screening performed in Italian idiopathic ALTE (IALTE) and sudden and unexpected infant death (SUID)/sudden infant death syndrome (SIDS) patients to search for genetic elements predisposing to these autonomic disorders, whose sudden manifestation may resemble congenital central hypoventilation syndrome (CCHS), caused by PHOX2B mutations

Summary

Introduction

Paired like homeobox 2b (PHOX2B) gene acts in the early development of the autonomic nervous system (ANS), regulating the expression of downstream genes that lead to neuronal differentiation [1]. Heterozygous mutations of the PHOX2B gene are responsible for congenital central hypoventilation syndrome (CCHS), a rare autosomal dominant genetic condition characterized by impaired response to hypercapnia and hypoxia due to compromised autonomic control of breathing [4,5,6]. Causative mutations are represented by triplet tandem duplications in exon 3 leading to polyalanine (polyAla) expansions, accounting for 90% of CCHS cases, in addition to missense, non-sense, and frameshift mutations responsible for the remaining patients. CCHS can occur either isolated or in association with other neural crest-derived disorders such as tumors of the sympathetic nervous system (TSNS) and Hirschsprung disease (HSCR), in which causative mutations and PHOX2B common variants have been shown to play a role as susceptibility genetic factors [7, 8]. Most patients need to be managed by ventilation only during asleep; in a small percentage of cases carrying the largest polyAla expansions, ventilation support is needed while awake [9]

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Conclusion