Central congenital hypoventilation

Gene: LBX1

I don't know

Comment on list classification: There is only one published family and mouse model available in support of the association. Hence, this gene should be rated amber with the current evidence.

Created: 13 Oct 2025, 9:23 a.m. | Last Modified: 13 Oct 2025, 9:23 a.m.

Panel Version: 1.5

Comment on phenotypes: This gene has been associated with relevant phenotype in OMIM (MIM #619483). This OMIM record has been accessed on 13 October 2025.

Created: 13 Oct 2025, 9:21 a.m. | Last Modified: 13 Oct 2025, 9:21 a.m.

Panel Version: 1.3

As reviewed by Ian Berry on the DDG2P panel, PMID:30487221 reported a consanguineous family with two male siblings diagnosed with congenital central hypoventilation syndrome and tested negative for PHOX2B variants. These two siblings were identified with a homozygous frameshift variant in exon 2 of LBX1 gene that alters the C terminus of the protein without affecting its homeodomain. Sanger sequencing of the entire family confirmed that the LBX1 frameshift variant segregated with the phenotype. There is also evidence from homozygous mice carrying the analogous variant (Lbx1FS/FS), which displayed respiratory deficits recapitulating the human phenotype.

Ian Berry's review also notes that there are two further cases in Genomics England dataset with comparable phenotypes and 2 further probands (with segregation) in other families via multinational collaboration, which have not yet been published in peer-reviewed publications.

In addition, all cases appear to have the same variant NM_006562.5: c.707del p.(Val236Alafs*59) which is suggested to be a Roma founder

This gene has been associated with amber rating on the 'Central Hypoventilation' panel from PanelApp Australia (https://panelapp-aus.org/panels/71/gene/LBX1/)

Created: 13 Oct 2025, 9:20 a.m. | Last Modified: 13 Oct 2025, 9:20 a.m.

Panel Version: 1.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Central hypoventilation syndrome, congenital, 3, OMIM:619483; central hypoventilation syndrome, congenital, 3, MONDO:0030539

Publications

• 30487221

Green List (high evidence)

Single sib-pair in PMID: 30487221 with congenital central hypoventilation syndrome, 1bp resulting in a frameshift in the terminal exon. Mouse model of the same variant expressed a protein with an altered C-terminal and replicated the human phenotype.

Subsequent unpublished studies (in process of publication): 2 further cases in CVA/GEL dataset with comparable phenotypes, 2 further probands (with segregation) in other families via multinational collaboration.

All cases appear to have the same variant NM_006562.5: c.707del p.(Val236Alafs*59) which may be a Roma founder.
Sources: Expert Review

Created: 8 Sep 2025, 7:26 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• PMID: 30487221

Variants in this GENE are reported as part of current diagnostic practice