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Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A ; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.

Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons.

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.

Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss. Yes

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25–38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.

La miocardiopatía dilatada aislada asintomática (MCD) se caracteriza por la dilatación y disfunción sistólica del ventrículo izquierdo, con la reducción de la fuerza de contracción del miocardio. Se considera que existe miocardiopatía dilatada familiar (MCDF) cuando dos o más miembros de una misma familia son diagnosticados de MCD idiopática. Debido a la enorme heterogeneidad genética y fenotípica de MCDF, el conocimiento de las alteraciones moleculares de esta enfermedad es limitado, por lo que se necesita mejorar la estrategia actual de diagnóstico y tratamiento. Para ello, la utilización de las nuevas tecnologías, como la secuenciación de nueva generación (NGS) entre las que se incluye la secuenciación del exoma completo (WES), puede ayudar en la búsqueda nuevos marcadores moleculares y dianas terapéuticas. El principal objetivo de este trabajo fue detectar los SNVs (Single Nucleotide Variants) que tienen una mayor relación con el desarrollo del MCDF. Para lograr este objetivo, se utilizaron diferentes herramientas bioinformáticas para el análisis de los datos obtenidos por WES de una familia de 6 miembros, dos de los cuales están diagnosticados con cardiopatía familiar dilatada de origen idiopático. Los resultados demuestran que el gen KCNJ12 juega un papel importante en la alteración de la estructura y conducción cardiaca, sugiriendo que la mutación P156L puede tener un papel patogénico en la miocardiopatía dilatada familiar. Mediante este trabajo se enfatiza la aplicación de WES en la identificación de mutaciones causales en esta enfermedad. La miocardiopatia dilatada aïllada asimptomàtica (MCD) es caracteritza per la dilatació i disfunció sistòlica del ventricle esquerre, amb la reducció de la força de contracció del miocardi. Es considera que hi ha miocardiopatia dilatada familiar (MCDF) quan dos o més membres d'una mateixa família són diagnosticats de MCD idiopàtica. A causa de l'enorme heterogeneïtat genètica i fenotípica de MCDF, el coneixement de les alteracions moleculars d'aquesta malaltia és limitat, de manera que es necessita millorar l'estratègia actual de diagnòstic i tractament. Per a això, la utilització de les noves tecnologies, com la seqüenciació de nova generació (NGS) entre les que s'inclou la seqüenciació de l'exoma complet (WES), pot ajudar en la recerca nous marcadors moleculars i dianes terapèutiques. El principal objectiu d'aquest treball va ser detectar els SNVs (single nucleotide Variants) que tenen una major relació amb el desenvolupament de l'MCDF. Per aconseguir aquest objectiu, es van utilitzar diferents eines bioinformàtiques per a l'anàlisi de les dades obtingudes per WES d'una família de 6 membres, dos dels quals estan diagnosticats amb cardiopatia familiar dilatada d'origen idiopàtic. Els resultats demostren que el gen KCNJ12 juga un paper important en l'alteració de l'estructura i conducció cardíaca, suggerint que la mutació P156L pot tenir un paper patogènic a la miocardiopatia dilatada familiar. Mitjançant aquest treball es emfatitza l'aplicació de WES en la identificació de mutacions causals en aquesta malaltia. Nonsyndromic isolated Dilated Cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction, a reduction in the myocardial force of contraction. When each of two or more closely related family members meet a formal diagnostic standard for idiopathic dilated cardiomyopathy diagnosis of familial dilated cardiomyopathy (FDCM) is made. Due to the enormous genetic and phenotypic heterogenicity of FDCM, knowledge of the molecular alterations of this disease is limited, so it is necessary to improve the current strategy of diagnosis and treatment. To this end, the use of new technologies, such as new generation sequencing (NGS), including complete exome sequencing (WES), can help in the search for new molecular markers and therapeutic targets. The main objective of this project was to detect the SNVs (Single Nucleotide Variants) that have a greater relationship with the development of the FDCM. To achieve this goal, different bioinformatics tools were used to analyze the data obtained by WES from a 6 members family, two of whom are diagnosed of idiopathic dilated cardiomyopathy. Results demonstrates that KCNJ12 gene play an important role in the alteration of the structure and cardiac conduction, and suggest that the P156L mutation may have a pathogenic role in familial dilated cardiomyopathy. This study emphasizes the application of WES in the identification of causal mutations in this disease.

Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis. Resumen Descripción del caso: Se reporta el caso de una paciente femenina de un año de edad, diagnosticada con Síndrome de Wiedemann-Steiner basado en la identificación de una nueva variante patogénica de novo de tipo frameshift en el gen KMT2A Mediante secuenciación de exoma usando el enfoque de trio, sumado a sus características clínicas. Hallazgos clínicos: las mutaciones en KMT2A causan el Síndrome de Wiedemann-Steiner, un desorden genético muy raro caracterizado por hipertricosis congénita, talla baja, retardo mental variable y fenotipo facial distintivo, los cuales se encuentran en la paciente reportada. Resultado: La Secuenciación de exoma completo encontró una variante de tipo frameshift: c.4177dupA (p. Ile1393Asnfs * 14) en KMT2A, este cambio a nivel génico genera una alteración de la unión específica a motivos CpG no metilados del DNA a la proteína. El genotipo y el fenotipo de la paciente fue comparado con los pacientes reportados previamente en la literatura. Relevancia clínica: En enfermedades con baja frecuencia como la aquí reportada es necesario establecer correlaciones genotipo-fenotipo que permitan establecer planes terapéuticos y de seguimiento. El análisis realizado no evidenció diferencias atribuibles a sexo o edad entre los pacientes diagnosticados con Síndrome de Weidemann-Steiner. La secuenciación de exoma permitió identificar causalidad en este caso, cuya característica principal de hipertricosis se asocia con alta heterogeneidad clínica y genética.

Antecedentes: El Colegio Americano de Genética Médica y Genómica (ACMG) publicó en el 2017 la segunda versión de las recomendaciones para reportar hallazgos secundarios, cuando a una persona se le ordena una prueba genética por otra indicación. Surgió el interés de determinar en una muestra de la población colombiana la prevalencia de hallazgos secundarios para los 59 genes asociados a 27 condiciones médicas que, por su gravedad, sí son diagnosticadas oportunamente pueden ser tratadas de forma adecuada. Métodos: Se realizó un estudio transversal analítico mediante examen de 160 pacientes (exomas), entre la edad de 1 y 79 años, procedentes de diferentes regiones del país. Se realizó la anotación de los 59 genes con bases de datos públicas, se clasificaron variantes con los criterios establecidos en la guía emitida por el ACMG y la Asociación de Patología Molecular y, posteriormente, se determinaron cuales se deberían reportar. Resultados: Se identificaron seis variantes en siete pacientes para los genes BRCA2, COL3A1, LDLR, MYBPC3, PKP2 y PMS2, con una prevalencia del 4,4%. No se encontró asociación entre las variables sociodemográficas con los hallazgos secundarios para informar (P>0,05). En estudios previos realizados se encontraron prevalencias que varían desde 0,59 al 21%. Conclusión: Dada la prevalencia encontrada y el impacto clínico de las variantes genómicas en la salud, es importante la búsqueda activa de hallazgos secundarios para que el profesional tratante pueda, a su vez, realizar el asesoramiento y manejo oportuno y adecuado al paciente con su grupo familiar. Background: In the year 2017, The American College of Medical Genetics and Genomics (ACMG) published the second version of their secondary findings reporting recommendations, for cases in which a person receives a genetic test for another indication. We decided to determine, using a sample of the Colombian population, the prevalence of secondary findings for the 59 genes associated with 27 medical conditions that, due to their severity, if diagnosed opportunely, can be properly treated. Methods: An analytical cross-sectional study was carried out by examining 160 patients (exomes), between the ages of 1 and 79 years, coming from different Colombian regions. Annotation of the 59 genes with public databases was performed, and variants were classified using the criteria established in the guide issued by the ACMG and the Association of Molecular Pathology and, subsequently, the ones to be reported were selected. Results: Six variants in seven patients for genes BRCA2, COL3A1, LDLR, MYBPC3, PKP2, and PMS2 were identified, with a prevalence of 4,4%. No association was found between the sociodemographic variables and the secondary findings (P>0,05). Previous studies have found prevalences ranging from 0,59 to 21%. Conclusion: Given the prevalence found and the clinical impact of genomic variants on health, it is important to actively search for secondary findings so that the treating professional can, in turn, perform timely and relevant counseling and management of the patients and their family.

Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1% of women. It has been estimated that the cause remains unexplained in >50% cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease’s genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations. The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41% of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology. Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability. The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss. © 2017 Quintero-Ronderos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.