Worse Brain MRI, Neurodevelopmental Outcomes Show No Link to dDNV Genes

The association with subgroups of gene variations based on expression or function should be assessed in larger studies, investigators say.

Worse brain magnetic resonance imaging (MRI) and neurodevelopmental outcomes were not associated with de novo variants in genes not previously associated with neurodevelopmental risk (dDNV-NR) overall, according to the results of a study published in JAMA Network Open.

However, the association of neurodevelopmental impairments with subgroups of gene variations based on expression or function should be assessed in larger studies, investigators said.

Investigators wanted to determine whether neurodevelopmental disabilities commonly associated with congenial heart disease (CHD) and dDNV-NRs were associated with neurological outcomes.

The cross-sectional study was conducted between September 2017 and June 2020 in 8 centers in the United States. Investigators included individuals who were aged 8 years or older with CHD and had available exome sequencing data. Individuals with pathogenic gene variants in CHD or neurodevelopment-related genes were excluded. Investigators matched cases and controls for age group, CHD class, and sex.

The main outcomes of the study included neurodevelopmental assessments of academic achievement, adaptive functioning, attention, anxiety, depression, executive function, fine motor skills, intelligence, language, memory, and social cognition. Additionally, investigators included 7 diffusion, functional, and structural brain MRI metrics.

Investigators included 221 individuals in the post-hoc analysis, as well as 219 in the case-control analysis.

Investigators found that cases and controls had similar primary outcomes, including math computation, reading composite, and spelling on the Wide Range Achievement Test, Fourth Edition, and secondary outcomes.

The dDNVs and/or rare putative loss-of-function variants (pLOFs) in chromatin-modifying genes were associated with lower mean verbal comprehension index scores at 91.4 for cases and 103.4 for controls; the Social Responsiveness Scale, Second Edition, scores at 57.3 and 49.4; and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores at 73.8 and 97.2, respectively.

Additionally, investigators determined that they were linked with higher likelihood of autism spectrum disorder at 28.6% compared with 5.2%.

The dDNVs and/or pLOFs in constrained genes were associated with lower mean scores on the Wide Range Assessment of Memory and Learning, Second Edition, for immediate story memory at 9.7 for cases and 10.7 for controls and immediate picture memory at 7.8 and 9, respectively.

Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores, with a mean of 55.5 for cases and 46.6 for controls.

Limitations of the study included the sample size, which investigators said increases the likelihood of a type 2 error.

Additionally, investigators noted that the genes could be constrained because of essential functions, which were unrelated to the structure of the brain and heart.

Furthermore, investigators said that survivor bias in the study could have reduced their ability to identify genes that were associated with earlier death in adults and older children in the study.

They concluded that the presence of dDNV-NR was not associated with adverse neurodevelopmental performance or brain MRI findings among individuals with CHD.


Morton SU, Norris-Brilliant A, Cunningham S, King E, et al. Association of potentially damaging de novo gene variants with neurologic outcomes in congenital heart disease. JAMA Netw Open. 2023;6(1):e2253191. doi:10.1001/jamanetworkopen.2022.53191

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