8 - Sulcal Pattern in Congenital Heart Disease is Associated with High-Brain Expressed and Chromatin-Modifying Gene Variants

Poster Number: 8
Publication Number: 8.109

Sarah U. Morton, Boston Children's Hospital/Harvard Medical School, Boston, MA, United States; Jane Newburger, Boston Children's Hospital, Waban, MA, United States; Elizabeth Goldmuntz, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Tom A. Miller, Maine Medical Center, Scarborough, ME, United States; Eileen King, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Chunyan Liu, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; evdokia anagnostou, University of Toronto, toronto, ON, Canada; Donald J. Hagler, University of California, San Diego, La Jolla, CA, United States; Wendy K. Chung, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Bruce D. Gelb, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Patrick S. McQuillen, UCSF Benioff Children's Hospital San Francisco, San Francisco, CA, United States; George A. Porter, University of Rochester, Rochester, NY, United States; Jonathan Seidman, Harvard Medical School, Boston, MA, United States; Christine Seidman, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States; Yufeng Shen, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Patricia Ellen Grant, Boston Children's Hospital, Boston, MA, United States; Kiho Im, Boston Children's Hospital, Boston, MA, United States

Background: Congenital heart disease (CHD) is associated with disruptions to brain growth and structure, which may be affected by genetic factors, abnormal fetal hemodynamics, and social/environmental factors. Specific forms of CHD are associated with abnormal sulcal patterning, and sulcal patterns correlate with neuropsychiatric outcomes such as executive function. Because primary sulcal patterns are under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD.

Objective: To determine if damaging variants in genes that function as chromatin modifiers (CM) or have high brain expression during development (HBE) are associated with sulcal pattern among patients with CHD.

Design/Methods: A Pediatric Cardiac Genomics Consortium cohort study (ClinicalTrials.gov NCT03070197) recruited CHD participants age ≥ 8 years to complete brain magnetic resonance imaging (MRI). Loss-of-function (LoF) variants in CM and HBE genes were identified in previously collected sequencing data. We characterized global pattern of primary sulci using a graph structure with the geometric and topological features of sulcal basins. Sulcal graph similarities were quantitatively computed in the left and right hemispheres and lobes for each of 92 CHD participants (mean age: 17.2 years) compared to a reference atlas. Mean sulcal pattern similarity to healthy controls was measured for each CHD participant. Multiple linear regression compared the sulcal pattern similarity value between CHD participants with and without LoF variants, controlling for age and sex.

Results: Among 92 CHD participants, CM and HBE LoF variants were found in 8 and 57 participants, respectively. CM variant genes were ARRB1, ASXL2, CHD1L, LIPN1, NEK11, PAX7, PRMT7, and USP16. Sulcal pattern similarity was lower in CHD participants with CM LoF variants in the right hemisphere (with vs without variants: mean similarity 0.740 vs 0.721, p=0.025), as well as the right frontal (0.755 vs 0.738, p=0.024), temporal (0.740 vs 0.720, p=0.030), and parietal lobes (0.721 vs 0.698, p=0.009). Sulcal pattern similarity was lower in the left hemisphere in CHD participants with HBE LoF variants (0.752 vs 0.749, p=0.016), as well as the left parietal lobe (0.737 vs 0.731, p=0.035).Conclusion(s): CM or HBE LoF variants were associated with reduced sulcal pattern similarity among participants with CHD. Regional specificity to sulcal alterations may reflect the role of specific CM or HBE genes in fetal brain development. Future work will examine associations between genetic and MRI correlates of neurodevelopmental outcomes.