Browsing by Subject "Dysmorphology"

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    Investigating Cardiac Class, Extracardiac Anomalies, and Dysmorphology Patterns Predictive of Mendelian Genetic Disorders in Pediatric Congenital Heart Disease
    (2024-05) Helm, Benjamin Michael; Wessel, Jennifer; Han, Jiali; Landis, Benjamin J.; Ware, Stephanie M.; Wetherill, Leah
    Congenital heart disease (CHD) is the most common class of birth defects, accounting for one-third of all congenital anomalies. There is a need to understand risk factors early in the CHD life course, as half of all mortalities affect infants. Approximately 20-30% of CHD is caused by Mendelian genetic diseases, and genetic risk factors strongly influence health outcomes. However, genetics evaluations are underutilized and unstandardized. We leveraged a clinical program standardizing genetics evaluations for pediatric CHD. Using a test-negative case-control design, we investigated novel phenotypic predictors of patients with Mendelian genetic disorders. In the first study of 588 patients (96% ≤1 year, 20.7% with a genetic diagnosis), we found that dysmorphic status was associated with two-fold increased risk of genetic diagnoses being identified, after adjusting for extracardiac anomalies (ECA) status. In the second work, we developed and applied a novel dysmorphology score for quantifying dysmorphology burden in 1,001 patients (95% ≤1 year, 23.4% with a genetic diagnosis). Using multivariable logistic regression models, we quantified associations between dysmorphology score, ECA status, and genetic diagnoses identified later by genetic testing. A clinical prediction model was developed to improve risk-stratification of patients with genetic disorders more objectively and based on quantification of dysmorphology. Last, we developed a novel method of body region dysmorphology (BRD) classification and investigated how BRD patterns were predictive of cytogenetic and monogenic diagnoses. Dysmorphism of the face, forehead, neck, and hands/feet regions were associated with genetic diagnoses, while adjusting for ECA status. Surprisingly, dysmorphism of the forehead was the strongest predictor of genetic diagnoses, including both chromosomal and monogenic disorders. We found 23.4% (n=234/1001) of patients had genetic diagnoses following standardized testing, and our novel phenotypic predictors, i.e., BRDs and dysmorphology score, will improve identification of rare genetic disorders. However, 8.7-13.1% of apparently isolated/non-dysmorphic patients had genetic disorders identified by genetic testing, highlighting the limitation of phenotype-driven prediction of genetic diagnoses. This work builds a foundation for investigating novel phenotypic associations with genetic causes of CHD, and future research will assess how early recognition of dysmorphology, ECA status, and CHD class predicts other long-term outcomes.
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    Performance of Dysmorphology‐Based Screening for Genetic Disorders in Pediatric Congenital Heart Disease Supports Wider Genetic Testing
    (Wiley, 2024) Helm, Benjamin M.; Helvaty, Lindsey R.; Conboy, Erin; Geddes, Gabrielle C.; Graham, Brett H.; Lah, Melissa; Wetherill, Leah; Landis, Benjamin J.; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
    Background: Dysmorphology evaluation is important for congenital heart disease (CHD) assessment, but there are no prior investigations quantifying the screening performance compared to standardized genetics evaluations. We investigated this through systematic dysmorphology assessment in CHD patients with standardized genetic testing in primarily pediatric patients with CHD. Methods: Dysmorphology evaluations preceding genetic testing results allowed us to test for associations between dysmorphic status and genetic diagnoses while adjusting for extracardiac anomalies (ECAs). We use a test-negative case-control design on a pediatric inpatient CHD cohort for our study. Results: Of 568 patients, nearly 96% of patients completed genetic testing, primarily chromosome microarray (CMA) ± exome sequencing-based genetic testing (493/568, 86.8%). Overall, 115 patients (20.2%) were found to have genetic diagnoses, and dysmorphic patients had doubled risk of genetic diagnoses, after ECA adjustment (OR = 2.10, p = 0.0030). We found that 7.9% (14/178) of ECA-/nondysmorphic patients had genetic diagnoses, which increased to 13.5% (26/192) in the ECA-/dysmorphic patients. Nearly 43% of ECA+/dysmorphic patients had genetic diagnoses (63/147). The positive predictive value of dysmorphic status was only 26.3%, and the negative predictive value of nondysmorphic status was 88.7%. Conclusions: Dysmorphology-based prediction of genetic disorders is limited because of diagnoses found in apparently isolated CHD. Our findings represent one of the only assessments of phenotype-based screening for genetic disorders in CHD and should inform clinical genetics evaluation practices for pediatric CHD.