morton_2023_oi_221502_1674145740.31597.pdf
Creators: name: Morton, Sarah U
name: Norris-Brilliant, Ami
name: Cunningham, Sean
name: King, Eileen
name: Goldmuntz, Elizabeth
name: Brueckner, Martina
name: Miller, Thomas A.
name: Thomas, Nina H.
name: Liu, Chunyan
name: Adams, Heather R.
name: Bellinger, David C
name: Cleveland, John
name: Cnota, James F.
name: Dale, Anders M.
name: Frommelt, Michele
name: Gelb, Bruce D.
name: Grant, P. Ellen
name: Goldberg, Caren S.
name: Huang, Hao
name: Kuperman, Joshua
name: Li, Jennifer S.
name: McQuillen, Patrick
name: Panigrahy, Ashok
name: A. Porter Jr, George
name: Roberts, Amy E.
name: Russell, Mark W.
name: Seidman, Christine E.
name: E. Tivarus, Madalina
name: Anagnoustou, Evdokia
name: J. Hagler Jr., Donald
name: Chung, Wendy K.
name: W Newburger, Jane
Publisher: name: Health Research Alliance
Year: 2023
Subjects: classificationCode: 320101
subject: Cardiology (incl. cardiovascular diseases)

description:   
<strong>Importance</strong>: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD) but medical and sociodemographic factors explain only one third of variance in outcome. 
<strong>Objective: </strong>To determine whether predicted damaging <em>de novo</em> variants (dDNV) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD. A <em>post-hoc</em> aim sought to determine whether some dDNV or rare predicted loss-of-function (pLOF) variants in specific gene categories are associated with outcomes. 
<strong>Design</strong>: Prospective observational study from September 2017-June 2020. 
<strong>Setting:</strong> Multicenter
<strong>Participants: </strong>Participants were drawn from the Pediatric Cardiac Genomics Consortium (n=197) or Single Ventricle Reconstruction trial (n=24). Inclusion criteria were CHD, ≥ age 8 years, and available exome sequencing data. Individuals with pathogenic variants in known CHD- or neurodevelopmental-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. All 221 participants were included in <em>post-hoc</em> analyses, and 219 in case/control analysis<em>. </em>
<strong>Exposure: </strong>Participants were heterozygous for (cases) or lacked (controls) predicted dDNV in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNV or pLOF variants in four gene categories: chromatin-modifying, constrained, high-brain-expressed, and neurodevelopmental risk. 
<strong>Main Outcomes and Measures:</strong> Neurodevelopmental and brain MRI metrics. 
<strong>Results</strong>: Participants were median 15.0 years, interquartile range [IQR] 10.0-21.2; 50% (110/219) were male. Case and control participants had similar outcomes. dDNV/pLOF variants in chromatin-modifying genes were associated with worse verbal comprehension (n=16 vs. 200 participants, mean±SD: 91.4±20.4 vs. 103.4±17.8, p=0.01), social responsiveness (n=15 vs. 183, 57.3±17.2 vs. 49.4±11.2, p=0.03), and working memory (n=5 vs. 87, 73.8±16.4 vs. 97.3±15.7, p=0.03), as well as higher likelihood of autism spectrum disorder (4/14 vs. 8/153, 28.6% vs. 5.2%, p = 0.01). dDNV/pLOF variants in constrained genes were associated with impaired memory (immediated story memory: n=95 vs. 122, 9.7±3.7 vs. 10.7±3.0, p=0.03; immediate picture memory: n= 93 vs 116, 7.8±3.1 vs. 9.0±2.9, p=0.01). Adults with dDNV/pLOF variants in high-brain-expressed genes had greater hyperactivity symptoms (n=42 vs 33, 55.5±15.4 vs. 46.6±12.3, p=0.01). 
<strong>Conclusions and Relevance</strong>: Neurodevelopmental outcomes are not associated with dDNV as a group, but may be worse in those with dDNV/pLOF variants in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific variants to brain function and structure.