Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes.

BACKGROUND: The most common cyanotic congenital heart disease (CHD) requiring management as a neonate is transposition of great arteries (TGA). Clinically, up to 50% of TGA patients develop some form of neurodevelopmental disability (NDD), thought to have a significant genetic component. A "ciliopathy" and links with laterality disorders have been proposed. This first report of whole genome sequencing in TGA, sought to identify clinically relevant variants contributing to heart, brain and laterality defects. METHODS: Initial whole genome sequencing analyses on 100 TGA patients focussed on established disease genes related to CHD (n = 107), NDD (n = 659) and heterotaxy (n = 74). Single variant as well as copy number variant analyses were conducted. Variant pathogenicity was assessed using the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. RESULTS: Fifty-five putatively damaging variants were identified in established disease genes associated with CHD, NDD and heterotaxy; however, no clinically relevant variants could be attributed to disease. Notably, case-control analyses identified significantly more predicted-damaging, silent and total variants in TGA cases than healthy controls in established CHD genes (P < .001), NDD genes (P < .001) as well as across the three gene panels (P < .001). CONCLUSION: We present compelling evidence that the majority of TGA is not caused by monogenic rare variants and is most likely oligogenic and/or polygenic in nature, highlighting the complex genetic architecture and multifactorial influences on this CHD sub-type and its long-term sequelae. Assessment of variant burden in key heart, brain and/or laterality genes may be required to unravel the genetic contributions to TGA and related disabilities.

Total weight loss after laparoscopic Roux-en-Y gastric bypass is influenced by preoperative weight loss: can we predict the outcome?

BACKGROUND: Preoperative weight loss (WL) is associated with higher postoperative WL at 1- to 2-year follow-up in patients who undergo laparoscopic Roux-en-Y gastric bypass (LRYGB). OBJECTIVE: To evaluate the possible association between preoperative and postoperative WL at 3-year follow-up and identify risk factors for insufficient WL. SETTING: A single-center prospective cohort study in the Netherlands. METHODS: Patients undergoing primary LRYGB and laparoscopic conversion from band to bypass (redo LRYGB) were instructed to lose weight preoperatively. Follow-up data were collected 1, 2, and 3 years postoperatively. WL was described as percentage total weight loss (%TWL) and percentage excess body mass index (BMI) loss. Patients were divided into 2 groups: group A lost any amount of weight; group B did not lose any weight or gained weight preoperatively. RESULTS: Group A consisted of 230 patients (median preoperative %TWL, 4.8%), and group B consisted of 46 patients (median preoperative %TWL, -1.3%). Median BMI at intake was 44.1 kg/m2. Baseline characteristics were similar. The %TWL and BMI for group A and B in the patients who underwent primary LRYGB at 1, 2, and 3 years was 32.2% (BMI, 28.6 kg/m2) versus 23.9% (BMI, 32.2 kg/m2), 31.8% (BMI, 28.9 kg/m2) versus 25.2% (BMI, 31.9 kg/m2), and 33.3% (BMI, 29.7 kg/m2) versus 21.9% (BMI, 34 kg/m2), respectively, all P < .05. In patients who underwent redo LRYGB no clinically significant differences in postoperative BMI were found. CONCLUSIONS: Preoperative WL in primary patients who undergo LRYGB can be useful to identify those at risk of inadequate postoperative WL. In patients who undergo redo LRYGB different risk factors should be considered for prediction of inadequate postoperative WL.