The homozygous long variant of 5-HTT gene in congenital central hypoventilation syndrome is associated with a modified resting CO2 set point

Nathalie Couque

doi:10.1186/s13023-026-04544-7

The homozygous long variant of 5-HTT gene in congenital central hypoventilation syndrome is associated with a modified resting CO2 set point

2026-08-12

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OA

AI

N

Nathalie Couque

B

Benjamin Dudoignon

P

Plamen Bokov

C

Christophe Delclaux *

DOI：10.1186/s13023-026-04544-7

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Central respiratory chemoreceptors are not definitively identified, but the retrotrapezoid nucleus is the main center whose absence is characteristic of congenital central hypoventilation syndrome (CCHS). Intense chemosensory stimuli activate circuits that are wake- or attention-promoting, such as the raphe, which modulates chemoreflexes. The main objective of our study was to assess whether residual central CO2 chemosensitivity in CCHS is related to serotonin transporter gene polymorphisms (homozygous long (ll) variant versus variants with short form, ss or sl). Twenty-three children with CCHS and PHOX2B pathogenic variants had peripheral (controller gain measurement) and central CO2 chemosensitivity assessment (hyperoxic, hypercapnic test), resting end-tidal PCO2 (PETCO2) measurement and 5-HTT polymorphism determination. The percentages of the ll, ls, and ss genotypes were 5/23 (22%), 14/23 (61%) and 4/23 (17%), respectively, and were not influenced by Phox2b mutations. Both central (0.16 L/min/mmHg [0.02; 0.33] versus 0.21 [0.06; 0.41], P = 0.551) and peripheral (0.47 L/min/mmHg [0.026; 0.71] versus 0.67 [0.24; 1.26], P = 0.602) CO2 chemosensitivities were not significantly different when comparing the L group (n = 5) and the S group (n = 18), while their resting PETCO2 values were different; the L group presented a higher PETCO2 value than the S group did (49.3 mmHg [46.9; 53.0] versus 42.0 [36.7; 44.8], P = 0.014). The CO2 chemosensitivity of children with CCHS was not related to 5-HTT transporter polymorphisms, whereas the ll homozygous variant contributed to resting alveolar hypoventilation.

Keywords:

Congenital central hypoventilation syndrome

Serotonin

5-HTT transporter polymorphism

CO2 chemosensitivity

CO2 set point

The homozygous long variant of 5-HTT gene in congenital central hypoventilation syndrome is associated with a modified resting CO2 set point

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