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SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability.

ABSTRACT: Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes. However, there is limited evidence demonstrating that genes causing CHD can produce NDD independent of hypoxia. A patient with hypoplastic left heart syndrome and gross motor delay presented with a de novo mutation in SMC5. Modeling mutation of smc5 in Xenopus tropicalis embryos resulted in reduced heart size, decreased brain length, and disrupted pax6 patterning. To evaluate the cardiac development, we induced the conditional knockout (cKO) of Smc5 in mouse cardiomyocytes, which led to the depletion of mature cardiomyocytes and abnormal contractility. To test a role for Smc5 specifically in the brain, we induced cKO in the mouse central nervous system, which resulted in decreased brain volume, and diminished connectivity between areas related to motor function but did not affect vascular or brain ventricular volume. We propose that genetic factors, rather than hypoxia alone, can contribute when NDD and CHD cases occur concurrently.

SUBMITTER: O'Brien MP

PROVIDER: S-EPMC10779392 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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<i>SMC5</i> Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability.

O'Brien Matthew P MP Pryzhkova Marina V MV Lake Evelyn M R EMR Mandino Francesca F Shen Xilin X Karnik Ruchika R Atkins Alisa A Xu Michelle J MJ Ji Weizhen W Konstantino Monica M Brueckner Martina M Ment Laura R LR Khokha Mustafa K MK Jordan Philip W PW

International journal of molecular sciences 20231228 1

Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes. However, there is limited evidence demonstrating that genes causing CHD can produce NDD independent of hypoxia. A patient ...[more]

PMID: 38203602

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Project description:BackgroundChildren with congenital heart defects have an increased risk of neurodevelopmental disability. The impact of environmental chemical exposures during daily life on neurodevelopmental outcomes in toddlers with congenital heart defects is unknown.MethodsThis prospective study investigated the impacts of early childhood exposure to mixtures of environmental chemicals on neurodevelopmental outcomes after cardiac surgery. Outcomes were assessed at 18 months of age using The Bayley Scales of Infant and Toddler Development-III. Urinary concentrations of exposure biomarkers of pesticides, phenols, parabens, and phthalates, and blood levels of lead, mercury, and nicotine were measured at the same time point. Bayesian profile regression and weighted quantile sum regression were utilized to assess associations between mixtures of biomarkers and neurodevelopmental scores.ResultsOne-hundred and forty infants were enrolled, and 110 (79%) returned at 18 months of age. Six biomarker exposure clusters were identified from the Bayesian profile regression analysis; and the pattern was driven by 15 of the 30 biomarkers, most notably 13 phthalate biomarkers. Children in the highest exposure cluster had significantly lower adjusted language scores by -9.41 points (95%CI: -17.2, -1.7) and adjusted motor scores by -4.9 points (-9.5, -0.4) compared to the lowest exposure. Weighted quantile sum regression modeling for the overall exposure-response relationship showed a significantly lower adjusted motor score (β = -2.8 points [2.5th and 97.5th percentile: -6.0, -0.6]). The weighted quantile sum regression index weights for several phthalates, one paraben, and one phenol suggest their relevance for poorer neurodevelopmental outcomes.ConclusionsLike other children, infants with congenital heart defects are exposed to complex mixtures of environmental chemicals in daily life. Higher exposure biomarker concentrations were associated with significantly worse performance for language and motor skills in this population.

Project description:BackgroundNeurodevelopmental outcomes programs for children with congenital heart disease (CHD) support early identification and intervention for developmental impairments; however, not all eligible children attend such programs. The purpose of our study was to examine factors, including sociodemographic, associated with cardiac neurodevelopmental outcomes program attendance.MethodsChildren with CHD born April 2013-April 2018 who underwent cardiac surgery before age 6 months were included. The primary outcome was at least one neurodevelopmental clinic visit, and secondary outcome was number of visits attended during the first two years of life. Predictor variables included maternal and infant characteristics, surgical data, geographic location of residence, and neighborhood-level socioeconomic metrics.ResultsOf 730 eligible infants, median age at surgery was 13 days (IQR 7-44), and 37% were Hispanic, 45% were non-Hispanic White, and 10% were non-Hispanic Black. Twenty-three percent lived >200 miles from the institution. A total of 462 (63%) attended at least one visit. On multivariable analysis, factors associated with attending at least once were Hispanic ethnicity (if living <200 miles from the institution or Spanish-speaking), older maternal age, and shorter driving time. On multivariable analysis of the secondary outcome, factors associated with a greater number of visits were Hispanic ethnicity (if living <200 miles from the institution), older maternal age, shorter driving time, and private health insurance.ConclusionsOur data demonstrate that Hispanic ethnicity and closer distance from the institution were associated with increased attendance in our neurodevelopmental program. Continued education on the importance of neurodevelopmental follow-up and making adaptations to current practices to reach all individuals with CHD will be important moving forward. Whether these higher rates of attendance improve neurodevelopmental outcomes for this specific population requires further research.

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SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability.

Publications

<i>SMC5</i> Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability.

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