SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability
Matthew P O'Brien1, Marina V Pryzhkova2,3, Evelyn M R Lake4
1Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Insights
Genetic mutations, not just hypoxia, can cause neurodevelopmental disability (NDD) in severe congenital heart disease (CHD) patients. A study found SMC5 gene mutations impact both heart and brain development, suggesting a genetic link to NDD in CHD.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- Severe congenital heart disease (CHD) is linked to neurodevelopmental disability (NDD) in up to 50% of patients.
- Hypoxia during or after cardiac surgery is the presumed cause of NDD in CHD.
- Recent findings suggest a genetic overlap between CHD and NDD, but direct evidence linking CHD genes to NDD independent of hypoxia is limited.
Purpose of the Study:
- To investigate the role of the SMC5 gene in concurrent CHD and NDD.
- To determine if mutations in CHD-associated genes can cause NDD independently of hypoxic events.
- To model the impact of SMC5 mutations on cardiac and neurological development.
Main Methods:
- Case study of a patient with hypoplastic left heart syndrome and NDD with a de novo SMC5 mutation.
- Xenopus tropicalis embryo modeling of smc5 mutation to assess heart and brain development.
- Conditional knockout (cKO) of Smc5 in mouse cardiomyocytes to evaluate cardiac function.
- Conditional knockout (cKO) of Smc5 in the mouse central nervous system to assess brain structure and connectivity.
Main Results:
- Xenopus embryos with smc5 mutation showed reduced heart size, decreased brain length, and disrupted pax6 patterning.
- SMC5 cKO in mouse cardiomyocytes led to depleted mature cardiomyocytes and abnormal contractility.
- SMC5 cKO in the mouse brain resulted in reduced brain volume and impaired motor function connectivity, without affecting vascular or ventricular volumes.
Conclusions:
- Genetic factors, specifically mutations in genes like SMC5, can contribute to neurodevelopmental disability in patients with congenital heart disease.
- The findings challenge the sole reliance on hypoxia as the cause of NDD in CHD, highlighting a direct genetic link.
- SMC5 plays a crucial role in both cardiac and central nervous system development, suggesting a shared genetic etiology for concurrent CHD and NDD.
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.
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