Myosin is the primary regulator of muscle strength and contractility. Here we show that three myosin genes, Myh6, Myh7, and Myh7b, encode related microRNAs (miRNAs) within their introns, which, in turn, control muscle myosin content, myofiber identity and muscle performance. Within the adult heart, the Myh6 gene, encoding a fast myosin, co-expresses miR-208a, which regulates the expression of two slow myosins and their intronic miRNAs, Myh7/miR-208b and Myh7b/miR-499, respectively. miR-208b and miR-499 are functionally redundant, and play a dominant role in the specification of muscle fiber identity by activating slow and repressing fast myofiber gene programs. The actions of these miRNAs are mediated by a collection of transcriptional repressors of slow myofiber genes. These findings reveal that myosin genes not only encode the major contractile proteins of muscle, but act more broadly to influence muscle function by encoding a network of intronic miRNAs that control muscle gene expression and performance.

The management of cardiovascular risk through lifestyle modification and pharmacotherapy is paramount to the prevention of cardiovascular disease. Epidemiological studies have identified obesity, dyslipidemia, diabetes, and hypertension as interrelated factors that negatively affect cardiovascular health. Recently, genetic and pharmacological evidence in model systems has implicated microRNAs as dynamic modifiers of disease pathogenesis. An expanded understanding of the function of microRNAs in gene regulatory networks associated with cardiovascular risk will enable identification of novel genetic mechanisms of disease and inform the development of innovative therapeutic strategies.

In response to physiological stimuli, skeletal muscle alters its myofiber composition to significantly affect muscle performance and metabolism. This process requires concerted regulation of myofiber-specific isoforms of sarcomeric and calcium regulatory proteins that couple action potentials to the generation of contractile force. Here, we identify Sox6 as a fast myofiber-enriched repressor of slow muscle gene expression in vivo. Mice lacking Sox6 specifically in skeletal muscle have an increased number of slow myofibers, elevated mitochondrial activity, and exhibit downregulation of the fast myofiber gene program, resulting in enhanced muscular endurance. In addition, microarray profiling of Sox6 knockout muscle revealed extensive muscle fiber-type remodeling, and identified numerous genes that display distinctive fiber-type enrichment. Sox6 directly represses the transcription of slow myofiberenriched genes by binding to conserved cis-regulatory elements. These results identify Sox6 as a robust regulator of muscle contractile phenotype and metabolism, and elucidate a mechanism by which functionally related muscle fiber-type specific gene isoforms are collectively controlled.calcium handling | myosin heavy-chain isoforms | slow-twitch fiber

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IMPORTANCE Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions. OBJECTIVE To compare the frequency of damaging variants in cancer risk genes among patients with CHD and control participants and identify associated clinical variables in patients with CHD who have cancer risk variants. DESIGN, SETTING, AND PARTICIPANTS This multicenter case-control study included participants with CHD who had previously been recruited to the Pediatric Cardiac Genomics Consortium based on presence of structural cardiac anomaly without genetic diagnosis at the time of enrollment. Permission to use published sequencing data from unaffected adult participants was obtained from 2 parent studies. Data were collected for this study from December 2010 to April 2019. EXPOSURES Presence of rare (allele frequency, <1 × 10 −5) loss-of-function (LoF) variants in cancer risk genes. MAIN OUTCOMES AND MEASURES Frequency of LoF variants in cancer risk genes (defined in the Catalogue of Somatic Mutations in Cancer-Cancer Gene Consensus database), were statistically assessed by binomial tests in patients with CHD and control participants. RESULTS A total of 4443 individuals with CHD (mean [range] age, 13.0 [0-84] years; 2225 of 3771 with reported sex [59.0%] male) and 9808 control participants (mean [range] age, 52.1 [1-92] years; 4967 of 9808 [50.6%] male) were included. The frequency of LoF variants in regulatory cancer risk genes was significantly higher in patients with CHD than control participants (143 of 4443 [3.2%] vs 166 of 9808 [1.7%]; odds ratio [OR], 1.93 [95% CI, 1.54-2.42]; P = 1.38 × 10 −12), and among CHD genes previously associated with cancer risk (58 of 4443 [1.3%] vs 18 of 9808 [0.18%]; OR, 7.2 [95% CI, 4.2-12.2]; P < 2.2 × 10 −16). The LoF variants were also nominally increased in 14 constrained cancer risk genes with high expression in the developing heart. Seven of these genes (ARHGEF12, CTNNB1, LPP, MLLT4, PTEN, TCF12, and TFRC) harbored LoF variants in multiple patients with unexplained CHD. The highest rates for LoF variants in cancer risk genes occurred in patients with CHD and

Background Genetic testing in pediatric primary dilated cardiomyopathy (DCM) patients has identified numerous disease‐causing variants, but few studies have evaluated genetic testing outcomes in this population in the context of patient and familial clinical data or assessed the clinical implications of temporal changes in genetic testing results. Methods and Results We performed a retrospective analysis of all patients with primary DCM who presented to our institution between 2008 and 2018. Variants identified by genetic testing were reevaluated for pathogenicity on the basis of current guidelines for variant classification. A total of 73 patients with primary DCM presented to our institution and 63 (86%) were probands that underwent cardiomyopathy‐specific gene testing. A disease‐causing variant was identified in 19 of 63 (30%) of cases, with at least 9/19 (47%) variants occurring de novo. Positive family history was not associated with identification of a causal variant. Reclassification of variants resulted in the downgrading of a large proportion of variants of uncertain significance and did not identify any new disease‐causing variants. Conclusions Clinical genetic testing identifies a causal variant in one third of pediatric patients with primary DCM. Variant reevaluation significantly decreased the number of variants of uncertain significance, but a large burden of variants of uncertain significance remain. These results highlight the need for periodic reanalysis of genetic testing results, additional investigation of genotype‐phenotype correlations in DCM through large, multicenter genetic studies, and development of improved tools for functional characterization of variants of uncertain significance.

Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by increased left ventricular wall thickness. While HCM is caused by pathogenic variants in any one of eight sarcomere protein genes, clinical expression varies considerably, even among patients with the same pathogenic variant. To determine whether background genetic variation or environmental factors drive these differences, we studied disease progression in 11 pairs of monozygotic HCM twins. The twin pairs were followed for 5 to 14 y, and left ventricular wall thickness, left atrial diameter, and left ventricular ejection fraction were collected from echocardiograms at various time points. All nine twin pairs with sarcomere protein gene variants and two with unknown disease etiologies had discordant morphologic features of the heart, demonstrating the influence of nonhereditable factors on clinical expression of HCM. Whole genome sequencing analysis of the six monozygotic twins with discordant HCM phenotypes did not reveal notable somatic genetic variants that might explain their clinical differences. Discordant cardiac morphology of identical twins highlights a significant role for epigenetics and environment in HCM disease progression.

Significance The genetic basis of isolated microtia, a congenital abnormality of the external ear, is poorly understood. Indigenous American (Amerindigenous) populations have the highest reported incidence of microtia. Here, we use whole genome sequencing to study microtia in Latin American families and identify a common microtia risk allele that is enriched among individuals with Amerindigenous ancestry. This allele is located in a regulatory region governing the expression of Roundabout 1 ( ROBO1 ) and Roundabout 2 ( ROBO2 ) in induced pluripotent stem cell–derived neural crest cells and is associated with a complex repeat sequence. These results identify a shared genetic basis for isolated microtia and other craniofacial abnormalities and account for, at least in part, the increased incidence of microtia in Amerindigenous populations.