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Hum Mutat. 2018 Feb;39(2):219-236. doi: 10.1002/humu.23365. Epub 2017 Nov 21.

Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome.

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Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
CNR- Neuroscience Institute, Milan, Italy.
UOC Genetica Medica, Istituto Giannina Gaslini, Genoa, Italy.


Heterozygous mutations in the PHOX2B gene are causative of congenital central hypoventilation syndrome (CCHS), a neurocristopathy characterized by defective autonomic control of breathing due to the impaired differentiation of neural crest cells. Among PHOX2B mutations, polyalanine (polyAla) expansions are almost exclusively associated with isolated CCHS, whereas frameshift variants, although less frequent, are often more severe than polyAla expansions and identified in syndromic CCHS. This article provides a complete review of all the frameshift mutations identified in cases of isolated and syndromic CCHS reported in the literature as well as those identified by us and not yet published. These were considered in terms of both their structure, whether the underlying indels induced frameshifts of either 1 or 2 steps ("frame 2" and "frame 3" mutations respectively), and clinical associations. Furthermore, we evaluated the structural and functional effects of one "frame 3" mutation identified in a patient with isolated CCHS, and one "frame 2" mutation identified in a patient with syndromic CCHS, also affected with Hirschsprung's disease and neuroblastoma. The data thus obtained confirm that the type of translational frame affects the severity of the transcriptional dysfunction and the predisposition to isolated or syndromic CCHS.


Hirschsprung's disease; PHOX2B; congenital central hypoventilation syndrome; dominant-negative; frameshift mutations; gain-of-function; loss-of-function; neuroblastoma

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