Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b

Abstract

Idiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970. A genetic basis of CCHS has been proposed because of the reports of four families with two affected children, because of mother-child transmission, and because of a recent report of a polyalanine expansion mutation in PHOX2b in a subset of CCHS subjects. We, therefore, studied genes pertinent to early embryologic development of the ANS including mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), engrailed-1 (EN1), TLX3, endothelin converting enzyme-1 (ECE1), endothelin-1 (EDN1), PHOX2a, and PHOX2b in 67 probands with CCHS, and gender- and ethnicity-matched controls. No disease-defining mutations were identified in MASH1, BMP2, EN1, TLX3, ECE1, EDN1, or PHOX2a. The 65/67 CCHS probands (97%) were found to be heterozygous for the exon 3 polyalanine expansion mutation identified previously in PHOX2b. Further, there was an association between repeat mutation length and severity of the CCHS/ANSD phenotype. Of the two probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 which truncated the protein and the other had no mutation in PHOX2b but had a previously reported EDN3 frameshift point mutation. The polyalanine expansion mutation was not found in any of 67 matched controls. Of 54 available families (including 97 unaffected parents), whose child carried the PHOX2b mutation, 4 parents demonstrated mosaicism for an expansion mutation identical to that seen in the CCHS cases, suggesting that not all mutations in affected probands with unaffected parents are de novo. We also studied four women with CCHS who were heterozygous for the PHOX2b mutation, each with one child. Three of the four children were also affected and had the same mutation, demonstrating autosomal dominant inheritance of the mutation. Assay of the PHOX2b polyalanine repeat mutation represents a highly sensitive and specific technique for confirming the diagnosis of CCHS. Identification of the CCHS mutation will lead to clarification of the phenotype, allow for prenatal diagnosis for parents of CCHS probands and adults with CCHS in future pregnancies, and potentially direct intervention strategies for the treatment of CCHS.

A Commentary on The importance of knowing from whence your PHOX2B mutation comes

“…Third, these results reiterate the need to carefully consider the mechanism chosen for PHOX2B testing among probands and among parents of probands in order to optimize management, assure safety and physiologic stability, and to determine risk of recurrence in subsequent offspring. This report supports previous findings [3][4][5] indicating inheritance of PHOX2B mutations from parental carriers with very low levels of somatic mosaicism (as low as 5% here). Although sequencing of the PHOX2B gene has become the most commonly available form of clinical testing in CCHS families, studies have shown it to be inadequate to identify low-level mosaicism.…”

“…Specifically, they have confirmed the autosomal dominant inheritance pattern 2,3 and described the incidence of somatic mosaicism or full mutation in parents of CCHS probands in the Japanese cohort (22%)-reflecting similar figures to the report (using the same methodology) as Bachetti et al 4 These results raise several important points in regard to genetic and physiologic testing procedures in CCHS families. First, the results emphasize the importance of genetic counseling for families in which a CCHScausing PHOX2B mutation is identified.…”

Analysis of RET, ZEB2, EDN3 and GDNF Genomic Rearrangements in Central Congenital Hyperventilation Syndrome Patients by Multiplex Ligation‐dependent Probe Amplification

“…A genetic background for isolated cases of CCHS has been established through findings of variants such as expansions of the polyalanine tract of exon 3 of the PHOX2b gene in up to 97% of patients Weese-Mayer et al, 2003;Gaultier et al, 2004;Berry-Kravis et al, 2006). Such variants, however, cannot account for the concomitant presentation of Hirschsprung's disease in up to 20% of CCHS patients, which suggests that other genes may be involved in the combined CCHS/HSCR phenotype.…”

“…The main genetic variants detected in CCHS patients have been mutations (deletions or expansions) in the PHOX2b gene, which in some series are present in up to 97% of isolated cases (Weese-Mayer et al, 2003). Most of these variants occur within the polyalanine tract in exon 3 Gaultier et al, 2004), yet 14 non-polyalanine repeat-expansion mutations have also been found in 184 CCHS patients and were linked to a more severe phenotype, with increased prevalence of continuous ventilatory dependence, Hirschsprung disease (HSCR) and neural crest tumours (Berry-Kravis et al, 2006).…”

Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion

“…About 90% of patients have de novo polyalanine expansion mutations in the polyalanine tract of 20 residues. [1][2][3][4][5][6] Approximately 5% of patients inherit polyalanine expansion mutations mostly from asymptomatic parents with somatic mosaicism and rarely from affected parents. Polyalanine expansion disorders constitute one family of homopolymer expansion disorders, including at least nine disorders.…”