Background: The cardiomyopathies, classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories based on the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive ( BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN ) or strong ( DSP ) evidence. Seven genes (14%) ( ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL ) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong; seven moderate). Notably, these 19 genes only explain a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high evidence genes, however genes lacking robust evidence are also commonly included. We recommend that high evidence DCM genes be used for clinical practice and to exercise caution when interpreting variants in variable evidence DCM genes.

Background: The cardiomyopathies are classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), and each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics was assembled to evaluate evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%) (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of the 19 genes classified as definitive, strong or moderate, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 commercially available genetic testing panels evaluated, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In a systematic curation of published evidence for genes considered relevant for monogenic DCM, 12 were classified as definitive or strong and seven as moderate evidence spanning 10 gene ontologies. Notably, these 19 genes only explain a minority of DCM cases, leaving the remainder of DCM genetic architecture incompletely addressed. While clinical genetic testing panels include most high evidence genes, genes lacking robust evidence are also commonly included. Until the genetic architecture of DCM is more fully defined, care should be taken in the interpretation of variable evidence DCM genes in clinical practice.

Numerous US states have implemented newborn screening for Krabbe disease (Krabbe NBS) as a result of legislative state mandates. While healthcare provider opinions toward Krabbe NBS have been documented, few studies have explored parental experiences and opinions regarding Krabbe NBS. Eleven families, who received a false‐positive Krabbe NBS result and received genetic counseling at an institution in central Ohio, were consented to participate in semistructured interviews. Interviews explored parents’ experiences throughout the NBS process and ascertained their opinions regarding Krabbe NBS. Three major themes emerged from thematic analysis: (1) improved understanding of the NBS process from a parent perspective, (2) the role of healthcare provider communication, and (3) the value of Krabbe NBS. Parents saw value in Krabbe NBS, despite many disclosing emotional distress and uncertainty throughout the NBS process. Parent experiences throughout the NBS process varied widely. Due to the expressed emotional distress, further research assessing effective communication during the NBS process is warranted. The researchers suggest additional NBS education for non‐genetics healthcare providers (i.e., nurses or primary care physicians) and further participation of genetic counselors in the NBS process may benefit families with a positive Krabbe NBS result.

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