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Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.

Doppler echocardiography assessment of left ventricular (LV) filling pressures at rest and during exercise is the most widely used imaging technique to assess LV diastolic function in clinical practice. However, a sizable number of patients evaluated for suspected LV diastolic function show an inconsistency between the various parameters included in the flowchart recommended by current Doppler echocardiography guidelines and results in an undetermined LV diastolic function. Current three-dimensional echocardiography technology allows obtaining accurate measurements of the left atrial volumes and functions that have been shown to improve the diagnostic accuracy and prognostic value of the algorithms recommended for assessing both LV diastolic dysfunction and heart failure with preserved ejection fraction. Moreover, current software packages used to quantify LV size and function provide also volume-time curves showing the dynamic LV volume change throughout the cardiac cycle. Examining the diastolic part of these curves allows the measurement of several indices of LV filling that have been reported to be useful to differentiate patients with normal LV diastolic function from patients with different degrees of diastolic dysfunction. Finally, several software packages allow to obtain also myocardial deformation parameters from the three-dimensional datasets of both the left atrium and the LV providing additional functional parameters that may be useful to improve the diagnostic yield of three-dimensional echocardiography for the LV diastolic dysfunction. This review summarizes the current applications of three-dimensional echocardiography to assess LV diastolic function.

AIMS: Transthoracic 3D echocardiography (3DE) has been shown to be feasible and accurate to measure right ventricular (RV) ejection fraction (EF) when compared with cardiac magnetic resonance (CMR). However, RV EF, either measured with CMR or 3DE, has always been reported as normal (RV EF > 45%) or abnormal (RV EF ≤ 45%). We therefore sought to identify the partition values of RV EF to stratify RV dysfunction in mildly, moderately, or severely reduced as we are used to do with the left ventricle. METHODS AND RESULTS: We used 3DE to measure RV EF in 412 consecutive patients (55 ± 18 years, 65% men) with various cardiac conditions who were followed for 3.7 ± 1.4 years to obtain the partition values which defined mild, moderate, and severe reduction of RV EF (derivation cohort). Then, the prognostic value of these partition values was tested in an independent population of 446 patients (67 ± 14 years, 58% men) (validation cohort). During follow-up, we recorded 59 cardiac deaths (14%) in the derivation cohort. Using K-Adaptive partitioning for survival data algorithm we identified four groups of patients with significantly different mortality according to RV EF: very low > 46%, 40.9% < low ≤ 46%, 32.1% < moderate ≤ 40.9%, and high ≤ 32.1%. To make the partition values easier to remember, we approximated them to 45%, 40%, and 30%. During 4.1 ± 1.2 year follow-up, 38 cardiac deaths and 88 major adverse cardiac events (MACE) (cardiac death, non-fatal myocardial infarction, ventricular fibrillation, or admission for heart failure) occurred in the validation cohort. The partition values of RV EF identified in the derivation cohort were able to stratify both the risk of cardiac death (log-rank = 100.1; P < 0.0001) and MACEs (log-rank = 117.6; P < 0.0001) in the validation cohort too. CONCLUSION: Our study confirms the independent prognostic value of RV EF in patients with heart diseases, and identifies the partition values of RV EF to stratify the risk of ca

Clinical expression of Ellis‐van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice‐site in‐frame change (c.1316–7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient‐derived fibroblasts and Evc–/– mouse embryonic fibroblasts showed that p.Arg622Ter is a loss‐of‐function mutation, whereas p.Arg663Pro and the splice‐site change c.1316–7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as “common atrium/AVCD with postaxial polydactyly” is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype‐phenotype correlations in this syndrome.

Morning hours are the period of the day characterized by the highest incidence of major cardiovascular events including myocardial infarction, sudden death or stroke. They are also characterized by important neurohormonal changes, in particular, the activation of sympathetic nervous system which usually leads to a rapid increase in blood pressure (BP), known as morning blood pressure surge (MBPS). It was hypothesized that excessive MBPS may be causally involved in the pathogenesis of cardiovascular events occurring in the morning by inducing hemodynamic stress. A number of studies support an independent relationship of MBPS with organ damage, cerebrovascular complications and mortality, although some heterogeneity exists in the available evidence. This may be due to ethnic differences, methodological issues and the confounding relationship of MBPS with other features of 24-hour BP profile, such as nocturnal dipping or BP variability. Several studies are also available dealing with treatment effects on MBPS and indicating the importance of long-acting antihypertensive drugs in this regard. This paper provides an overview of pathophysiologic, methodological, prognostic and therapeutic aspects related to MBPS.

Ellis-van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.