Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2Deletion Syndrome

Am J Hum Genet. 2015 May 7;96(5):753-64. doi: 10.1016/j.ajhg.2015.03.007. Epub 2015 Apr 16.

Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2Deletion Syndrome.

Mlynarski EE1Sheridan MB1Xie M2Guo T3Racedo SE3McDonald-McGinn DM4Gai X5Chow EW6Vorstman J7Swillen A8Devriendt K8Breckpot J8,Digilio MC9Marino B10Dallapiccola B9Philip N11Simon TJ12Roberts AE13Piotrowicz M14Bearden CE15Eliez S16Gothelf D17Coleman K18Kates WR19Devoto M20Zackai E4Heine-Suñer D21Shaikh TH22Bassett AS6Goldmuntz E23Morrow BE3Emanuel BS24International Chromosome 22q11.2Consortium.

Comment: Approximately 65% of individuals with 22q11.2 deletion syndrome have cardiovascular malformations (CVMs), but the factors impacting the risk for developing a CVM are not known.  Mylnarski and colleagues hypothesized that, in patients with 22q11.2 deletion, additional copy number variants (CNVs) act as genetic modifiers and impact the risk for development of CVMs.  This study included 2 separate cohorts each consisting of unrelated white individuals of European descent.  Genotyping for CNVs was performed using SNP arrays.  In the first cohort (N=562) duplication of 12p13.31 was more frequently observed in patients with CVM (18 of 363) than those without CVM (1/199) (p=3.12 x 10-3).  This finding was then replicated in a 2nd cohort of 387 patients with 22q11.2 deletion (p=3.3 x 10-2).  Combining the 2 cohorts, 12p13.31 duplication was observed in 35 of 603 patients (5.8%) with CVM as opposed to 4 of 346 (0.7%) without CVM (p=2.68 x 10-4).  To put these frequencies in context, this CNV has previously been observed in 2.2% of healthy individuals.  The authors conclude that the responsible gene within this duplicated region is SLC2A3, which encodes a facilitated glucose transporter, and they demonstrate that this gene is expressed in the developing mouse brain, pharyngeal arches, and outflow tracts.  There was no observed difference in the frequency of deletion of SLC2A3 between those with or without CVM.  There also was no difference in deletion or duplication of SLC2A3 between patients with non-syndromic CVMs and healthy controls. The authors postulate that the duplication of SLC2A3 in combination with 22q11.2 deletion may together act as a “two-hit model” for the development of CVM in some patients.