Short QT syndrome

Gene: SLC4A3

I don't know

See table 1/figure 3 of Campuzano 2018, gene associated with Short QT syndrome.

Created: 25 Sep 2019, 1:22 p.m. | Last Modified: 25 Sep 2019, 1:22 p.m.

Panel Version: 1.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 18382206
• 19862833
• 30420954

I don't know

Comment on list classification: Demoted from Green to Amber based on the previously submitted review.

Created: 27 Nov 2019, 1:14 p.m. | Last Modified: 27 Nov 2019, 1:14 p.m.

Panel Version: 1.25

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.

Created: 18 Nov 2019, 2:45 p.m. | Last Modified: 18 Nov 2019, 2:45 p.m.

Panel Version: 1.23

Comment on mode of inheritance: Changed from Unknown back to Monoallelic after discussion with Anna de Burca (Genomics England).

Created: 3 Sep 2019, 8:40 a.m. | Last Modified: 3 Sep 2019, 8:40 a.m.

Panel Version: 1.13

Red List (low evidence)

No associated phenotype on OMIM

Created: 25 Mar 2019, 4:30 p.m.

1 variant associated with SQT on HGMD

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
Unknown

I don't know

PMID 29167417 reports this variant in 2 unrelated families with apparent Short QT syndrome. All carrier relatives have QTc <370 which is on the shorter side of normal but not necessarily diagnostic for SQT (300-320ms). Proband in both families was a SCD but very few other relatives with symptoms of arrhythmia (several episodes of syncope as teenagers). Whilst this variant clearly segregates with a shortened QTc interval in the larger of these families no hard evidence that it is responsible for causing SCD or has the potential to cause arrhyhthmia. Most arrhythmia causing genes to date are involved with cation exchange across the membrane. This is a Chloride exchange gene which is a little known mechanism for arrhythmia.

Created: 25 Jan 2019, 12:52 p.m.

Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. One variant was identified in two unrelated families. The variant segregates with short QT in both families and an Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which was rescued by wildtype SLC4A3, but not by the variant (PMID: 29167417).

Created: 19 Nov 2018, 11:09 a.m.

Green List (high evidence)

The Nature Communications paper reporting this association presents strong evidence for causal link to SQTS. This variant of the SQTS was found from exome sequencing. Mutation leads to altered pHi and decrease in intracellular chloride, which in turn abbreviates repolarization. The final mediator(s) of these actions remain to be elucidated.
Sources: Literature

Created: 17 Oct 2018, 10:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
short QT; ventricular fibrillation; cardiac arrest

Publications

• PMID: 29167417
• 29697308