Double somatic mosaicism in Marfan syndrome.

Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.

Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation.

BACKGROUND: Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled. OBJECTIVES: This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups. METHODS: We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects). RESULTS: Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%). CONCLUSIONS: Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.

Clinical Relevance of the Systematic Analysis of Copy Number Variants in the Genetic Study of Cardiomyopathies.

Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic cause. Next-Generation Sequencing (NGS) has expanded the genes studied for CMs; however, the yield is still around 50%. The systematic study of Copy Number Variants (CNVs) could contribute to improving our diagnostic capacity. These alterations have already been described as responsible for cardiomyopathies in some cases; however, their impact has been rarely assessed. We analyzed the clinical significance of CNVs in cardiomyopathies by studying 11,647 affected patients, many more than those considered in previously published studies. We evaluated the yield of the systematic study of CNVs in a production context using NGS and a novel CNV detection software tool v2.0 that has demonstrated great efficacy, maximizing sensitivity and avoiding false positives. We obtained a CNV analysis yield of 0.8% that fluctuated depending on the type of cardiomyopathy studied (0.29% HCM, 1.41% DCM, 1.88% ARVC, 1.8% LVNC, 1.45% RCM), and we present the frequency of occurrence for 18 genes that agglutinate the 95 pathogenic/likely pathogenic CNVs detected. We conclude the importance of including in diagnostic tests a systematic study of these genetic alterations for the different cardiomyopathies.

Penetrance of Dilated Cardiomyopathy in Genotype-Positive Relatives.

BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.

Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

Emerging Themes in Genetics of Hypertrophic Cardiomyopathy: Current Status and Clinical Application.

Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of unexplained left ventricular hypertrophy (LVH), with wall thickness ≥ 1.5 cm, is a phenotype in search of a diagnosis, which is most often a genetically determined, cardiac exclusive, or systemic disorder. Familial evaluation and genetic testing are required for definitive diagnosis. The role of genetic findings in predicting development of disease, outcomes, and increasingly to guide management is evolving with access to larger data sets. The specific mutation and sex of the patient are important determinants that ultimately are likely to guide management. The genetic/familial evaluation is influenced by the accuracy of the clinical diagnosis and the extent/expertise of the genetic laboratory. Genetic testing in a patient with unexplained LVH without systemic manifestations will yield a definite/likely pathogenetic mutation in a sarcomere (30%-50%), regulatory/functional (10%-15%) or metabolic/syndromic (< 5%) gene associated with Mendelian inheritance. The importance of oligo- and polygenic determinants, usually in the absence of Mendelian inheritance, is under investigation with important implications, particularly related to familial evaluation and definition of risk of disease development in relatives of probands. The results of genetic testing are increasingly important in management strategies related to the use of the implantable cardioverter defibrillator for prevention of sudden death, use of myosin inhibitors for refractory symptoms in patients with and without outflow tract obstruction, and-on the immediate horizon-gene therapy. This review will focus on genetic and outcome data in sarcomeric HCM, and minor causative genes with robust evidence of their association will also be considered.

Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers.

Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.

Abordaje de las cardiopatías familiares desde la Medicina genómica / Approach to familial heart diseases from Genomic Medicine

Resumen Las cardiopatías familiares son un grupo de enfermedades con alta heterogeneidad clínica y genética. Debido a que pueden heredarse y a su asociación con la muerte súbita, se recomienda efectuar un estudio clínico y genético del individuo afectado y su familia a través de una unidad especializada. Con la implementación de la secuenciación masiva se ha facilitado el acceso a los estudios genéticos en la práctica clínica de forma más rutinaria. Sin embargo, dada la gran cantidad de información obtenida se hacen necesarios el análisis y la interpretación adecuada de los resultados para garantizar un diagnóstico correcto. Este nuevo modelo de medicina amplía nuestra comprensión sobre estas patologías, gracias a que optimiza el diagnóstico, da una mejor aproximación pronóstica de los pacientes e identifica individuos asintomáticos en riesgo. Este artículo pretende realizar una revisión de la arquitectura genética de las enfermedades cardíacas hereditarias y proporcionar un enfoque práctico acerca de la utilidad de la Medicina genómica en el diagnóstico, la estratificación del riesgo y el estudio familiar en pacientes con este tipo de patologías.

Abstract The familial heart diseases are a group of diseases with high clinical and genomic heterogeneity. As they can be inherited and are associated with sudden death, it is recommended to perform a clinical and genetic study of the individual affected, as well as the family, in a specialised unit. The implementation of massive sequencing has meant that access to genetic studies is available in the most routine clinical practice. However, due to the large amount of information obtained, the results have to analysed and interpreted to ensure a correct diagnosis. This new medicine model widens the understanding of these diseases, as due to the diagnosis being optimised, it provides a more accurate prognosis for the patients, and identifies asymptomatic individuals at risk. A review is presented on the genetic architecture of heritable heart disease and provides a practical approach on the usefulness of Genomic Medicine in the diagnosis, risk stratification, and the familial study in patients with these types of heart diseases.

Relationship between overall child development and caries severity in Chilean three-year-old preschool children / Relación entre el desarrollo infantil integral y la severidad de caries en preescolares chilenos de 3 años

Abstract: to determine the relationship between caries and overall child development in three-year-old children in the cities of Linares and Talca, Chile, 2014-2015. Method: Cross-sectional study conducted in a sample of 170 preschool children attending daycare centers in Linares and Talca. Four dimensions of child development (language, cognition, motor skills and socio-emotional development) were qualitatively assessed using the child learning and development test (TADI, for its acronym in Spanish). Nutritional development was calculated with the weight/height index. Caries history was assessed by the dmft index and compromised tissue quantification. Statistical analysis was performed using Pearson's rho, ANOVA, Student’s t-test, Fisher’s exact test and Kruskal-Wallis. Results: A negative linear correlation was observed between dmft and total TADI score (r=-0.20, p=0.00), and the dimensions of language (r=-0.19, p=0.01), cognition (r=-0.18, p=0.02) and socio-emotional development (r=-0.21, p=0.01). Preschoolers with a dmft of >6.5 had a lower average TADI score than those with a dmft of <2.6 (p=0.009). There were no statistically significant differences in the level of compromised tissue quantification between preschool children with normal and altered development. No statistically significant association between dmft and nutritional development was found. Conclusion: A relationship between caries severity and overall child development in three-year-old preschool children was observed. Longitudinal studies are required to assess causality.

Resumen: determinar la relación entre la severidad de caries y el desarrollo infantil integral en preescolares de tres años de las ciudades Linares y Talca durante el período 2014- 2015. Método: Estudio transversal con una muestra de 170 preescolares asistentes a jardines infantiles de Linares y Talca. El test de aprendizaje y desarrollo infantil (TADI) evaluó el desarrollo en cuatro dimensiones (lenguaje, cognición, motricidad y socioemocionalidad). El desarrollo nutricional se calculó con el índice peso/talla. Se evaluó la historia de caries mediante ceod y compromiso del tejido dentario. Se realizó análisis estadístico con rho de Pearson, ANOVA, t de student, test exacto de Fisher y Kruskall Wallis. Resultados: Se observó una correlación lineal negativa entre ceod y el puntaje total del TADI (r=-0,20, p=0,00), y las dimensiones de lenguaje (r=-0,19, p=0,01), cognición (r=-0,18, p=0,02) y socioemocionalidad (r=-0,21, p=0,01). Los preescolares con ceod >6,5 tuvieron un promedio TADI menor que aquellos con ceod <2,6 (p=0,009). No hubo diferencias estadísticamente significativas entre el compromiso del tejido dentario entre preescolares con desarrollo normal y alterado. No se observó asociación estadísticamente significativa entre ceod y desarrollo nutricional. Conclusión: Se observó una relación entre la severidad de caries y el desarrollo infantil integral en preescolares de tres años. Se requiere de estudios longitudinales para evaluar su causalidad.