Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Experiences of the Molecular Diagnosis of Fragile X Syndrome in Ecuador.

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on polymerase chain reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12-43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature; however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests and establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

Multi-institutional experience of genetic diagnosis in Ecuador: National registry of chromosome alterations and polymorphisms.

BACKGROUND: Detection of chromosomal abnormalities is crucial in various medical areas; to diagnose birth defects, genetic disorders, and infertility, among other complex phenotypes, in individuals across a wide range of ages. Hence, the present study wants to contribute to the knowledge of type and frequency of chromosomal alterations and polymorphisms in Ecuador. METHODS: Cytogenetic registers from different Ecuadorian provinces have been merged and analyzed to construct an open-access national registry of chromosome alterations and polymorphisms. RESULTS: Of 28,806 karyotypes analyzed, 6,008 (20.9%) exhibited alterations. Down syndrome was the most frequent autosome alteration (88.28%), followed by Turner syndrome (60.50%), a gonosome aneuploidy. A recurrent high percentage of Down syndrome mosaicism (7.45%) reported here, as well as by previous Ecuadorian preliminary registries, could be associated with geographic location and admixed ancestral composition. Translocations (2.46%) and polymorphisms (7.84%) were not as numerous as autosomopathies (64.33%) and gonosomopathies (25.37%). Complementary to conventional cytogenetics tests, molecular tools have allowed identification of submicroscopic alterations regions or candidate genes which can be possibly implicated in patients' symptoms and phenotypes. CONCLUSION: The Ecuadorian National Registry of Chromosome Alterations and Polymorphisms provides a baseline to better understand chromosomal abnormalities in Ecuador and therefore their clinical management and awareness. This data will guide public policy makers to promote and financially support cytogenetic and genetic testing.

Turner syndrome associated with Down syndrome: about a case / Síndrome Turner asociado a síndrome Down: a propósito de un caso

The coexistence of double aneuploidy of Down and Turner syndromes is rare; most cases have been due to double mitotic errors. The objective of the study was to report a case with monosomy of the X chromosome and trisomy of chromosome 21, in mosaic variety, highlighting the phenotypic effect that the presence of different chromosomal abnormalities can produce and compare with those reported in the literature. A 10-year-old Ecuadorian female, born to a multipregnant mother with 46 years at conception, is seen in consultation with a predominant clinical phenotype of Down syndrome, associated with menarche, presence of pubic and axillary villu, where a karyotype is verified 45 X[7]/47XX+ 21 [3]/46, X, der (X)(: p11.1-> q11.1)[1]/46,XX [1]. The present case is a double Turner-Down aneuploidy, with predominantly X monosomy cell line, who shows important mental retardation and some signs of puberal development not usually in Turner syndrome. These features highlight the clinical importance of doing a karyotype in mental retardation cases and searching low mosaics of another aneuploidies in atypical cases. Its complex chromosomal formula and support with molecular cytogenetics allowed diagnostic confirmation and genetic counseling.

La coexistencia de doble aneuploidía de los síndromes de Down y Turner es rara; la mayoría de los casos se han debido a dobles errores mitóticos. Reportar un caso con trisomía del cromosoma 21 y monosomía del cromosoma en X, en variedad mosaico, que curiosamente presenta un despertar puberal precoz y comparar con los reportados en la literatura. Paciente ecuatoriana de sexo femenino, de 10 años de edad, nacida de madre multigesta con 46 años a la concepción, que es vista en consulta con fenotipo clínico predominante de Síndrome Down, asociado a menarquia y telarquia, donde se constata un cariotipo. El presente caso es el primero informado de mosaicismo de doble aneuploidía de Turner-Down asociado con un despertar puberal precoz. Su fórmula cromosómica compleja y el apoyo con la citogenética molecular permitió la confirmación diagnostica y la asesoría genética.

Variantes citogenéticas en pacientes con síndrome de Turner diagnosticadas en un hospital de tercer nivel de atención en Ecuador / Cytogenetic variants in patients with Turner syndrome diagnosed in a third level care hospital in Ecuador

Resumen Introducción: El Síndrome de Turner (ST) es una alteración cromosómica sexual causada por la ausencia parcial o completa del cromosoma X, además de mosaicismos y otras alteraciones estructurales del cromosoma X o Y; está presente en 1 de 2500 nacidas vivas. Objetivo: Describir las variantes citogenéticas de pacientes con síndrome de Turner y evaluar su asociación con el fenotipo de presentación y la edad del diagnóstico. Método: Estudio retrospectivo de corte transversal de una serie de 82 casos de síndrome de Turner. Los cariotipos fueron realizados utilizando el medio RPMI-1640; las preparaciones de cromosomas se obtuvieron utilizando técnicas estándar y se analizaron mediante bandas GTG con una resolución de 400-450 bandas, donde se contó con 20-50 metafases para reducir la probabilidad de no detección de mosaicismo. Resultados: 45 (55.6%) fueron diagnosticadas, con monosomía clásica del cromosoma X, mientras 29 (35,8%) mostraron anomalías estructurales del cromosoma X y 7 (8,6%) se asociaron a mosaicos numéricos del cromosoma X. Solo 21 (26%) pacientes fueron diagnosticadas por debajo de los 12 años, mientras el resto 60 (74%) se detectaron entre la adolescencia y la adultez. La baja estatura fue una característica universal en todos los grupos de estudio. Conclusiones: Las fórmulas cromosómicas en el síndrome de Turner pueden ser muy variadas y tener diversas implicaciones en el fenotipo; se destaca la baja talla como un criterio clínico relevante en la sospecha clínica.

Abstract Introduction: Turner Syndrome (TS) is a sexual chromosomal alteration caused by the partial or complete absence of the X chromosome, in addition to mosaicisms and other structural alterations of the X or Y chromosome; It is present in 1 in 2,500 live births. Objective: To describe the cytogenetic variants of Turner syndrome patients and to evaluate their association with the phenotype at presentation and age at diagnosis. Methods: Retrospective cross-sectional study of a series of 82 cases of Turner syndrome. Karyotypes were performed using RPMI-1640 medium; Chromosome preparations were obtained using standard techniques and analyzed by GTG banding with a resolution of 400-450 bands where 20-50 metaphases were counted to reduce the probability of missing mosaicism. Results: 45 (55.6%) were diagnosed with classic monosomy of the X chromosome, while 29 (35.8%) showed structural abnormalities of the X chromosome and 7 (8.6%) were associated with numerical mosaics of the X chromosome. Only 21 (26%) patients were diagnosed under 12 years of age, while the rest 60 (74%) were detected between adolescence and adulthood. Short stature was a universal characteristic in all study groups. Conclusions: The chromosomal formulas in Turner syndrome can be variable and have different implications in the phenotype; short stature stands out as a relevant clinical criterion in clinical suspicion.

Novel EYA1 variants causing Branchio-oto-renal syndrome.

INTRODUCTION: Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal malformations. Pathogenic mutations have been discovered in several genes such as EYA1, SIX5, and SIX1. However, nearly half of those affected reveal no pathogenic variant by traditional genetic testing. METHODS AND MATERIALS: Whole Exome sequencing and/or Sanger sequencing performed in 10 unrelated families from Turkey, Iran, Ecuador, and USA with BOR syndrome in this study. RESULTS: We identified causative DNA variants in six families including novel c.525delT, c.979T > C, and c.1768delG and a previously reported c.1779A > T variants in EYA1. Two large heterozygous deletions involving EYA1 were detected in additional two families. Whole exome sequencing did not reveal a causative variant in the remaining four families. CONCLUSIONS: A variety of DNA changes including large deletions underlie BOR syndrome in different populations, which can be detected with comprehensive genetic testing.

Varones 46, XX: a propósito de dos casos genéticamente distintos / Males 46, XX: Presentation of Two Genetically Different Cases

Introducción Los desórdenes de diferenciación sexual son condiciones clínicas en las que existe una discrepancia entre el sexo cromosómico y el sexo fenotípico de un individuo. Esas condiciones suelen resultar angustiantes para los pacientes y sus familias e incluso para el equipo médico tratante debido a la dificultad en diagnosticarlas. Objetivo Presentar las características clínicas, genéticas y hormonales de dos varones con desórdenes de diferenciación sexual. Método Se realizó un estudio descriptivo basado en la revisión y análisis de datos de la historia clínica y la confrontación de los resultados con reportes similares. Resultados Se observaron dos individuos con fenotipo masculino y diagnóstico de hipogonadismo hipergonadotrófico con cariotipo 46, XX. El primer caso presentó testes pequeños y azoospermia, mientras que el segundo caso presentó baja talla, criptorquidea bilateral congénita y escrotos hipoplásicos. En ambos pacientes se exploró la presencia del gen SRY, confirmando su presencia en el primer caso y ausencia en el segundo caso. Conclusiones El diagnóstico genético-molecular actual apela a la combinación de técnicas tradicionales junto a técnicas modernas, como secuenciación por paneles genéticos a fin de identificar etiológicamente los desórdenes de diferenciación sexual. La presentación de esos casos aún se considera rara debido a su baja tasa de frecuencia poblacional, por lo que su reporte siempre resultará útil a la comunidad científica ya que muestran las distintas formas de presentación clínica y el manejo multidisciplinario de esos casos en diferentes contextos clínicos

Introduction Disorders of Sexual Development are clinical conditions in which a discrepancy between the chromosomal sex and the phenotypic sex occurs in an individual. These conditions are often distressing for patients and their families and even for the medical team due to the difficulty of diagnosing them. Objective The aim of this study was to present the clinical, genetic and hormonal characteristics of two males with sexual differentiation disorders. Method A descriptive study was performed based on the review and analysis of the clinical history data and the comparison of the results with similar cases reported. Results Two individuals with a male phenotype and a diagnosis of hypogonadotropic hypogonadism with 46, XX karyotype were observed. The first case presented small testes and azoospermia, while the second case presented low height, congenital bilateral cryptorchid and hypoplastic scrotums. The SRY gene was explored in both patients, and it was confirmed its presence in the first case and its absence in the second case. Conclusions The current molecular-genetic diagnosis calls for the combination of traditional techniques combined with modern techniques, such as the genetic panel sequencing, to identify etiologically the Disorders of Sexual Development. The presentation of these cases is even considered rare because of their low population frequency rate, so their report is always useful to the scientific community, for they show the different ways of the clinical disease presentation and the multidisciplinary management of these cases in different clinical contexts.

Ataxia espinocerebelosa tipo 2: diagnóstico clínico y molecular de dos casos atendidos en el Hospital de Especialidades de las Fuerzas Armadas N°1 / Spinocerebellar ataxia type 2: clinical and molecular diagnosis of two cases treated at the Armed Forces N°1 Hospital

La ataxia espinocerebelosa tipo 2 (SCA2) es una enfermedad neurodegenerativa causada por la expansión del trinucleótido CAG en el exón 1 del gen Ataxina-2 (ATXN2), situado en la región cromosómica 12q23-24. Este es el primer reporte de diagnóstico molecular realizado en Ecuador para esta enfermedad. Presentación de los casos Dos pacientes ecuatorianos de género masculino de 39 y 46 años de edad fueron remitidos al Servicio de Genética Médica del Hospital de Especialidades de las Fuerzas Armadas Nº1 para identifcar el tipo de ataxia espinocerebelosa presente en cada caso. Para ambos pacientes, la evaluación clínica evidenció síntomas compatibles con una SCA2, el análisis genealógico mostró un patrón de herencia autosómico dominante y el diagnóstico molecular confrmó que la ataxia espinocerebelosa presente era de tipo 2. Conclusión El diagnóstico específco de las ataxias espinocerebelosas debe basarse principalmente en una correlación fenotípica-genotípica, la cual involucra evaluaciones clínicas, análisis genealógico y estudios genéticos moleculares para cada caso. La SCA2 constituye un tipo de enfermedad cuyo diagnóstico implica complejidades clínicas y genéticas, concluyendo que este proceso debe efectuarse con la inclusión del asesoramiento genético familiar, siendo el comienzo del manejo integral de esta enfermedad

Premisas éticas en el diagnóstico prenatal de defectos congénitos en Cuba / Ethical premises in the prenatal diagnosis of congenital defects in Cuba

El propósito de este trabajo es presentar una propuesta de premisas éticas para la práctica del diagnóstico prenatal de defectos congénitos. Se realizó un estudio sistemático, profundo y crítico sobre el tema y sobre los resultados de investigaciones realizadas en población cubana y los derivados de talleres realizados con la participación de especialistas de la Red Nacional de Genética Médica; para su elaboración se tuvieron en cuenta los principios éticos más universalmente aceptados y recomendados por la OMS y otros organismos internacionales, así como las resoluciones y leyes cubanas relacionadas con este tema. Se presentan normativas generales, sobre el diagnóstico prenatal y el aborto selectivo, el asesoramiento genético y el revelado de información; esta propuesta se complementa con otras normativas propias de la investigación científica y relacionadas con el consentimiento informado, las investigaciones que involucran pacientes, aspectos de la ética profesional y de las publicaciones científicas. Estas normativas en su conjunto conforman las premisas éticas que garantizan el respeto a los derechos y a la dignidad de las personas que son atendidas en los servicios de asesoramiento genético y diagnóstico prenatal y formarán parte de un manual para la provisión de servicios en la red de genética médica de Cuba

The objective of this paper was to submit a proposal of ethical premises for prenatal diagnosis of congenital defects. An in-depth systematic and critical study was conducted on the topic and on the results of research works carried out with the Cuban population and those of workshops where the National Network of Medical Genetics experts participated. For their preparation, the universally accepted ethical principles that are recommended by WHO and other international bodies, as well as the Cuban resolutions and laws in this regard were all taken into account. Some general standards on prenatal diagnosis and selective abortion and on the approach to genetic counseling and the disclosure of information were presented. This proposal was supplemented with other standards inherent to the scientific research, since during prenatal diagnosis practice, some research works can emerge, the results of which may be published, that is, informed consent, research involving patients, ethical aspects of scientific publications and professional ethics elements. These standards are the ethical premises that guarantee the respect to the rights and to the dignity of those persons who are served by the genetic counselling and prenatal diagnosis services, and will be part of a manual for the provision of services in the medical genetic network of Cuba

Análisis de las malformaciones congénitas detectadas por el programa alfafetoproteína-ultrasonido genético / Analysis of the congenital malformations detected by the alpha-fetoprotein-genetic ultrasound program

La alfafetoproteína es una glicoproteína específica del plasma fetal, cuya determinación en suero materno se realiza entre las 15 y 19 semanas de gestación. Para conocer el comportamiento del programa alfafetoproteína-ultrasonido genético en el municipio 10 de Octubre se realizó esta investigación. En ella se encontró que 862 gestantes presentaron alfafetoproteína elevada en suero materno en el período analizado, y las principales causas encontradas dependientes de la madre fueron: el error en la fecha de última menstruación, seguida de la amenaza de aborto; y las malformaciones congénitas más frecuentemente encontradas fueron los defectos de cierre del tubo neural, seguidos de las malformaciones cardiovasculares.

Características clinicogenética y epidemiológica de los defectos por reducción de extremidades informados al Registro de Malformaciones Congénitas / Clinical, genetic and epidemiologic characteristics of defects due to reduction of extremities informed to the congenital malformations registration

Se revisaron los expedientes de todos los niños con defectos congénitos por reducción de extremidades, notificados al Registro de Malformaciones Congénitas de Santiago de Cuba en el período comprendido de 1997 al 2004, así como los protocolos de las muertes fetales o abortos inducidos terapéuticamente, de donde se extrajeron los datos primarios de interés. La frecuencia de dichas anomalías fue de 0,43 por cada 1 000 nacidos vivos, con predominio de los defectos terminales transversos y de la afectación unilateral de los miembros superiores. No se obtuvo información relevante sobre la exposición a algún agente teratogénico conocido. Las formas aisladas primaron sobre las asociadas