Abstract
Hirschsprung disease (HSCR) is a congenital malformation of the hindgut resulting from a disruption of neural crest cell migration during embryonic development. It has a complex genetic aetiology with several genes involved in its pathogenesis. PHOX2B plays a key function in the development of neural crest derivatives, and heterozygous mutations cause a complex dysautonomia associating HSCR, Congenital Central Hypoventilation Syndrome (CCHS) and neuroblastoma (NB) in various combinations. In order to determine the role of PHOX2B in isolated HSCR, we performed a mutational screening in a cohort of 207 Spanish HSCR patients. Our most relevant finding has been the identification of a de novo and novel deletion (c.393_410del18) in a patient with HSCR. Results of in silico and functional assays support its pathogenic effect related to HSCR. Therefore our results support that PHOX2B loss-of-function is a rare cause of HSCR phenotype.
Highlights
The paired-like homeobox 2b gene (PHOX2B) encodes a transcription factor involved in the development of several noradrenergic neuron populations in mice
PHOX2B is the major disease causing gene in Congenital Central Hypoventilation Syndrome (CCHS, OMIM 209880), that is associated with sympathetic tumour and Hirschsprung disease (HSCR, OMIM 142623) in 5 and 20% of cases respectively
We have detected a total of 5 novel PHOX2B variants in the mutational screening of the 207 HSCR patients, consisting in 2 heterozygous nucleotidic variants and 3 heterozygous indels (Table 2)
Summary
The paired-like homeobox 2b gene (PHOX2B) encodes a transcription factor involved in the development of several noradrenergic neuron populations in mice. In some cases PHOX2B point mutations/deletions have been reported in patients without CCHS and presenting neuroblastoma (NB, OMIM 256700), HSCR or both [6,8,9]. The second case correspond to several members of one family harboring the p.Arg100Leu point mutation, that resulted in either isolated HSCR, ganglioneuroma or NB [9]. Taking all these data together, PHOX2B can be regarded as an interesting candidate gene to be further studied in isolated forms of HSCR. Almost all isolated HSCR patients harbour either a heterozygous mutation of the coding sequence or, more often, a hypomorphic allele located in a conserved sequence in intron 1 and acting as a transcriptional enhancer [11,12]
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