Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene-specific.

Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE-related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation of Hedgehog or Nodal signaling pathways, both known as major triggers of HPE, has been shown to play a role in the pathogenesis of CHD, including structural defects and left-right asymmetry defects. In this study, individuals with various types of HPE were investigated clinically and by genomic sequencing. Cardiac phenotypes were assessed in 434 individuals with HPE who underwent targeted sequencing. CHDs were identified in 8% (n = 33) of individuals, including 10 (30%) cases of complex heart disease. Only four individuals (4/33) had damaging variants in the known HPE genes STAG2, SIX3, and SHH. Interestingly, no CHD was identified in the 37 individuals of our cohort with pathogenic variants in ZIC2. These findings suggest that CHD occurs more frequently in HPE-affected individuals with or without identifiable genetic variants, and this co-occurrence may be genetically driven and gene-specific.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Identifying and improving the "ground truth" of race in disparities research through improved EMR data reporting. A systematic review.

BACKGROUND: Studies about racial disparities in healthcare are increasing in quantity; however, they are subject to vast differences in definition, classification, and utilization of race/ethnicity data. Improved standardization of this information can strengthen conclusions drawn from studies using such data. The objective of this study is to examine how data related to race/ethnicity are recorded in research through examining articles on race/ethnicity health disparities and examine problems and solutions in data reporting that may impact overall data quality. METHODS: In this systematic review, Business Source Complete, Embase.com, IEEE Xplore, PubMed, Scopus and Web of Science Core Collection were searched for relevant articles published from 2000 to 2020. Search terms related to the concepts of electronic medical records, race/ethnicity, and data entry related to race/ethnicity were used. Exclusion criteria included articles not in the English language and those describing pediatric populations. Data were extracted from published articles. This review was organized and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement for systematic reviews. FINDINGS: In this systematic review, 109 full text articles were reviewed. Weaknesses and possible solutions have been discussed in current literature, with the predominant problem and solution as follows: the electronic medical record (EMR) is vulnerable to inaccuracies and incompleteness in the methods that research staff collect this data; however, improved standardization of the collection and use of race data in patient care may help alleviate these inaccuracies. INTERPRETATION: Conclusions drawn from large datasets concerning peoples of certain race/ethnic groups should be made cautiously, and a careful review of the methodology of each publication should be considered prior to implementation in patient care.

Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa.

BACKGROUND: Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease. METHODS: Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands and parents when available. For genes of high interest, we conducted functional studies in Drosophila using a cardiac-specific RNA interference-based gene silencing system. RESULTS: The 3 most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the Genome Aggregation Database (v3). Nineteen loss of function variants were identified using the genome-wide distribution of selection effects for heterozygous protein-truncating variants (shet). Nine genes caused a significant mortality when silenced in the Drosophila heart, including 4 novel disease genes not previously associated with CHD (UBB, EIF4G3, SREBF1, and METTL23). CONCLUSIONS: This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in understudied populations. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01952171.