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. 2025 Apr;18(2):e004895.
doi: 10.1161/CIRCGEN.124.004895. Epub 2025 Mar 28.

Dysmorphology-Based Prediction Model for Genetic Disorders in Infants With Congenital Heart Disease

Benjamin M Helm  1   2 , Leah Wetherill  1 , Benjamin J Landis  3 , Stephanie M Ware  1
Affiliations

Dysmorphology-Based Prediction Model for Genetic Disorders in Infants With Congenital Heart Disease

Benjamin M Helm et al. Circ Genom Precis Med. 2025 Apr.

Abstract

Background: Genetic disorders are prevalent in patients with congenital heart disease (CHD), but genetic evaluations are underutilized and nonstandardized. We sought to quantify a dysmorphology score and develop phenotype-based prediction models for genetic diagnoses in CHD.

Methods: We used a test-negative case-control study of inpatient infants (<1 year) with CHD undergoing standardized genetic evaluations. We quantified a novel dysmorphology score and combined it with other clinical variables used in multivariable logistic regression models to predict genetic diagnoses identified by genetic testing.

Results: Of 1008 patients, 24.1% (243/1008) had genetic diagnoses identified. About half of the cohort were either nondysmorphic or mildly dysmorphic with dysmorphology scores ≤2. There were higher dysmorphology scores according to CHD class (P=0.0007), extracardiac anomaly-positive status (P<0.0001), female sex (P=0.05), and genetic diagnosis identified (P<0.0001). Multivariable logistic regression models quantified this effect further: each +1 increase in the dysmorphology score was associated with a 17% to 20% increased risk of genetic diagnoses (odds ratios, 1.17-1.20, P<0.0001). Extracardiac anomaly-positive status remained a stronger predictor of genetic diagnoses (odds ratios, 2.81-3.39). Nonetheless, about 10% of the cohort were minimally dysmorphic (dysmorphology scores ≤2), had isolated CHD, and were found to have genetic diagnoses, indicating that dysmorphology-based screening can be used to risk-stratify but not exclude genetic diagnoses.

Conclusions: The dysmorphology score is a novel screen for patients with CHD at high risk of having genetic diagnoses identified by genetic testing, including disorders not easily recognized by clinicians. We used these results to develop predicted probability plots for genetic diagnoses in patients with CHD.

Keywords: genetic testing; humans; infant; odds ratio; phenotype.

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Conflict of interest statement

None.

References

    1. Cowan JR, Ware SM. Genetics and genetic testing in congenital heart disease. Clin Perinatol. 2015;42:373–393, ix. doi: 10.1016/j.clp.2015.02.009 - DOI - PubMed
    1. van der Bom T, Zomer AC, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJ. The changing epidemiology of congenital heart disease. Nat Rev Cardiol. 2011;8:50–60. doi: 10.1038/nrcardio.2010.166 - DOI - PubMed
    1. Zaidi S, Brueckner M. Genetics and Genomics of Congenital Heart Disease. Circ Res. 2017;120:923–940. doi: 10.1161/circresaha.116.309140 - DOI - PMC - PubMed
    1. Connor JA, Hinton RB, Miller EM, Sund KL, Ruschman JG, Ware SM. Genetic testing practices in infants with congenital heart disease. Congenit Heart Dis. 2014;9:158–167. doi: 10.1111/chd.12112 - DOI - PubMed
    1. Buckley JR, Kavarana MN, Chowdhury SM, Scheurer MA. Current Practice and Utility of Chromosome Microarray Analysis in Infants Undergoing Cardiac Surgery. Congenit Heart Dis. 2015;10:E131–138. doi: 10.1111/chd.12241 - DOI - PMC - PubMed

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