Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants

Q1Q1Artículo original445-453Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness

Definición de Subtipos del Síndrome de Usher en Población Colombiana

<h3>Resumen</h3><p><strong>Introducción.</strong> El Síndrome de Usher (USH), de herencia autosómica recesiva, se caracteriza por sordera congénita sensorial, Retinitis Pigmentosa y disfunción vestibular. Se conocen 3 tipos clínicos y 12 subtipos genéticos. En Colombia no se conocen las frecuencias de los subtipos genéticos ni las mutaciones más frecuentes.</p><p><strong>Objetivo.</strong> El objetivo de este trabajo fue definir el subtipo genético en 72 individuos con USH e identificar las mutaciones causantes de la enfermedad.</p><p><strong>Métodos</strong>. Se identificaron 72 individuos con USH de diferentes ciudades del país. Se realizó análisis de haplotipos para los 12 loci asociados a USH hasta el momento y análisis mutacional de los exones con mayor frecuencia de mutaciones reportadas en los genes USH.</p><p><strong>Resultados</strong>. Se logró definir el subtipo genético en 23 individuos y se identificó la mutación causal en 14. Se identifi caron dos mutaciones en el gen MYO7A, la p.R634X y la p.R1986X; y tres en el gen USH2A, la c.2299delG, la p.R334W, y la g.G129T.</p><p><strong>Conclusión.</strong> Se logró identificar el subtipo genético en el 31.9% y la mutación causal en el 19.4% de la población.</p><p><span>Palabras clave:</span> Síndrome de Usher, Retinitis Pigmentosa, Sordera, Hipoacusia Sensorial.</p><h3><span>Usher Syndrome Subtypes Definition in Colombian Population </span></h3><h3>Abstract</h3><p><strong>Introduction.</strong> Usher Syndrome (USH), is an autosomal recessive disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and variable vestibular areflexia. Three clinical types and 12 genetic subtypes have been described. In Colombia, frequencies of genetic subtypes and more frequent mutations are unknown.</p><p><strong>Objective.</strong> The aim of this work was to defi ne the genetic subtype in Colombian population with USH.</p><p><strong>Methods.</strong> 72 individuals with USH were selected from different cities around the country. Haplotype analysis was performed to identify segregation to any of the 12 known USH loci. Mutational analysis of some exons was performed in USH genes.</p><p><strong>Results.</strong> Genetic subtype of 23 individuals and pathological mutation in 14 were identified. Two mutations were identifi ed in MYO7A gene, p.R634X and p.R1986X; and three in the USH2A gene, c.2299delG, p.R334W, and g.G129T.</p><p><strong>Conclusion</strong>. Genetic subtype was identified in 31.9% of the population and pathologic mutation in 19.4%.</p><p><span>Key words:</span> Usher Syndromes, Retinitis Pigmentosa, Deafness, Hearing Loss, Sensorineural.</p&gt

Phenotypic characterization of retinitis pigmentosa associated with deafness

Introducción. El síndrome de Usher es una alteración genética caracterizada por la asociación de retinitis pigmentaria y sordera. Sin embargo, hay casos con familias en las cuales, a pesar de presentarse dicha asociación, no se puede diagnosticar un síndrome de Usher ni ninguno otro. Objetivo. Reevaluar fenotípicamente a 103 familias con diagnóstico previo de posible síndrome de Usher o retinitis pigmentaria asociada con sordera. Materiales y métodos. Se revisaron las historias clínicas de 103 familias con un posible diagnóstico clínico de síndrome de Usher o retinitis pigmentaria asociada con sordera. Se seleccionaron las familias cuyo diagnóstico clínico no correspondía a un síndrome de Usher típico. Los afectados fueron valorados oftalmológica y audiológicamente. Se analizaron variables demográficas y clínicas. Resultados. Se reevaluaron 14 familias cuyo diagnóstico clínico no correspondía al de síndrome de Usher. De las familias con diagnóstico inicial de síndrome de Usher típico, el 13,6 % recibieron uno posterior de “retinitis pigmentaria asociada con sordera”, de “otro síntoma ocular asociado con hipoacusia”, o en forma aislada en una misma familia, de “retinitis pigmentaria” o “hipoacusia”. Conclusiones. Es fundamental el estudio familiar en los casos en que la clínica no concuerda con el diagnóstico de síndrome de Usher típico. En los pacientes con retinitis pigmentaria asociada con sordera, el diagnóstico clínico acertado permite enfocar los análisis moleculares y, así, establecer un diagnóstico diferencial. Es necesario elaborar guías de nomenclatura en los casos con estos hallazgos atípicos para orientar a médicos e investigadores en cuanto a su correcto manejo.Q4Q3Introduction: There are several syndromes that associate retinitis pigmentosa with deafness or hearing loss. The most frequent is Usher syndrome, a genetic disorder of autosomal recessive inheritance, which, in some cases, is accompanied by vestibular dysfunction. However, there are cases of families that despite having retinitis pigmentosa associated with deafness, cannot be classified as Usher or other syndromes due to additional findings. Objective: To reassess the phenotypes of 103 families previously diagnosed as possible Usher syndrome and/or retinitis pigmentosa associated with deafness. Materials and methods: We conducted a descriptive and retrospective study by reviewing the medical records of 103 families with a probable clinical diagnosis of Usher syndrome and/or retinitis pigmentosa associated with deafness. Families whose clinical diagnosis did not correspond to the typical Usher syndrome were selected and evaluated ophthalmologically and audiologically. Demographic and clinical variables were analyzed. Results: We selected and then reevaluated 14 families and 55 individuals as they did not correspond to a clinical diagnosis of Usher syndrome; 13.6% of the families initially considered to have typical Usher syndrome were later diagnosed with retinitis pigmentosa associated with deafness, another ocular symptom associated with hearing loss, retinitis pigmentosa, or isolated hearing loss in the same family. Conclusions: Family studies are essential in cases where the symptoms do not match the typical Usher’ syndrome. In the cases of retinitis pigmentosa associated with deafness, a correct clinical diagnosis allows for focusing on the molecular analyses to establish a differential diagnosis. The need for nomenclature guidelines on these atypical findings is relevant to aid physicians and researchers in the best approach to these cases.https://orcid.org/0000-0001-5439-5560https://orcid.org/0000-0001-9380-0792https://orcid.org/0000-0002-3925-1451https://orcid.org/0000-0001-8297-3970Revista Nacional - IndexadaBN

Genetic counseling in usher syndrome : linkage and mutational analysis of 10 colombian families

Q4Q415-27Usher Syndrome (US), an autosomal recessive disease, is characterized by retinitis pigmentosa (RP), vestibular dysfunction, and congenital sensorineural deafness. There are three recognized clinical types of the disorder. In order to improve genetic counseling for affected families, we conducted linkage analysis and DNA sequencing in 10 Colombian families with confirmed diagnosis of US (4 type I and 6 type II). Seventy-five percent of the US1 families showed linkage to locus USH1B, while the remaining 25% showed linkage to loci USH1B and USH1C. Among families showing linkage to USH1B we found two different mutations in the MYO7A gene: IVS42-26insTTGAG in exon 43 (heterozygous state) and R634X (CGA-TGA) in exon 16 (homozygous state). All six US2 families showed linkage to locus USH2A. Of them, 4 had c.2299delG mutation (1 homozygote state and 3 heterozygous); in the remaining 2 we did not identify any pathologic DNA variant. USH2A individuals with a 2299delG mutation presented a typical and homogeneous retinal phenotype with bilateral severe hearing loss, except for one individual with a heterozygous 2299delG mutation, whose hearing loss was asymmetric, but more profound than in the other cases. The study of these families adds to the genotype-phenotype characterization of the different types and subtypes of US and facilitates genetic counseling in these families. We would like to emphasize the need to perform DNA studies as a prerequisite for genetic counseling in affected families

Nutritional management results in a family with phenylketonuria following genetics diagnosis : dissertations around monitoring and adherence to treatment

Introducción: Aunque ciertamente la Fenilcetonuria (PKU) no sea un desorden metabólico común en Colombia, médicos generales, pediatras y genetistas deben estar alerta de su presencia y, deben propender por un diagnóstico completo que permita iniciar un manejo nutricional ade-cuado temprano. De manera que no sólo es importante el diagnóstico, sino la asesoría genética apropiada, el manejo y seguimiento. Sólo de esta manera se logran minimizar las secuelas y en especial, el daño neurológico propio de esta alteración metabólica, dado que es una de las pocas patologías genéticas en la que es posible ofrecer algún tipo de manejo que evite daños devastadores y ofrezca así un mejor pronóstico. Es igualmente importante estar atentos a los procesos del sistema de salud colombiano, que impone trabas y demoras en los manejos y tratamientos de estas enfermedades poco frecuentes, pues son causa de baja adherencia, suspensión de tratamientos y empeoramiento clínico de nuestros pacientes, con deterioro irre-versible muy negativo en estas familias afectadas vulnerables e indefensas. Objetivo: En este trabajo se realizó seguimiento durante un año y medio de evolución bajo manejo nutricional a una familia colombiana con diagnóstico clínico, bioquímico y molecular de Fenilcetonuria (PKU). Materiales y Métodos: A una familia colombiana con diagnóstico de Fenilcetonuria, con 4 individuos afectados, se le hizo el seguimiento clínico de su evolución durante un año y medio, mientras recibían el tratamiento consistente en el manejo nutricional adecuado para su enfer-medad de base, la ingesta de preparados de fórmulas comerciales adecuadas y seguimiento de pruebas bioquímicas y de evolución clínica con o sin tratamiento. Resultados: Se presentan los resultados de la evolución clínica bajo tratamiento con manejo nutricional adecuado durante un año de observación clínica y su evolución medio año después de haber suspendido el tratamiento y manejo. Se resalta la evolución con y sin el manejo médico recomendado. Conclusiones: Se enfatiza la importancia de estar atentos a sospechar la enfermedad, del diagnóstico temprano y el manejo dietario adecuado que implique una verdadera prevención de secuelas. Así mismo se discute el manejo en los sistemas de salud del tratamiento de este tipo de enfermedades raras, la falta de mecanismos de adherencia al tratamiento, la ausencia de programas de seguimiento y los efectos deletéreos de suspender un manejo y tratamiento exitoso.Artículo de investigación339-348Introduction:Phenylketonuria (PKU) is not a common metabolic disorder in Colombia indeed, but still general practitioners, pediatricians and geneticists should be aware of its presence and should promote a comprehensive diagnosis, allowing a proper early nutritional management. So not only diagnosing it is important, but the appropriate genetic counseling, management and monitoring as well. Accomplishing all these, we will minimize sequelae and especially neurological damage, since it is one of the few genetic diseases in which it is possible to offer some kind of management that avoid devastating damage, thus leading to a better prognosis. It is equally important to follow carefully all processes of the Colombian Health System, which imposes barriers and delays in handling rare diseases, because these barriers and delays are the cause of low adhesion, suspension of treatments and clinical worsening of patients, with very negative irreversible deterioration in affected, vulnerable and helpless patients and their families. Objective:To perform a follow-up throughout a year and a half of evolution under nu-tritional management, to a Colombian family with clinical, biochemical and molecular diagnosis of phenylketonuria (PKU). Materials and methods:Treatment consisting of nutritional mana-gement suitable for underlying disease, intake of adequate commercial formulas and monitoring of biochemical tests and clinical evolution were given to 4 affected individuals of a Colombian family diagnosed with phenylketonuria, followed-up for a year and a half. Results: We present the results of clinical evolution under treatment with suitable nutritional management for a year of clinical observation and its evolution for half a year after treatment withdrawal. Evolution with and without medical management is highlighted. Conclusions:We emphasize the importance of being aware of the disease, since early diagnosis and appropriate management involving diet gives a true prevention of sequelae. Likewise we discussed management of health system procedures for treatment of rare diseases, to avoid lack of adherence, absence of monitoring programs and deleterious effects of suspensión of a successful treatment

Detection of hearing loss in newborns : definition of a screening strategy in Bogotá, Colombia

Q4Q276-81Objective: To describe the results from the hearing screening protocol adopted in a Hospital in Colombia emphasizing the importance of performing screening on an outpatient basis, when the newborn is more than 24 h old. Methods: A prospective study at Hospital Universitario San Ignacio in Bogota, Colombia was carried out, from May 1st, 2016 to Nov 30th, 2017, the study sample included 2.088 newborns examined using transient otoacoustic emissions. Results: We obtained written consent from the parents of 1.523 newborns and 24 individuals (1.6%) failed the first stage of the screening, nine cases unilateral and 15 bilateral. A total of nine neonates (0,6%) failed the second screening test, six cases unilateral and three bilateral. Four (0,3%) did not return to the second test. Our false altered screening rate was 0.7%. Conclusions: In a developing country with limited human and economic resources, in which newborn early discharge is the norm, a newborn hearing screening program linked to infants’ check-ups, that uses otoacoustic emissions after 48 h of life, seems a feasible option compare to the standard US protocol aiming to conduct hearing screening prior to discharge

Risk factors associated with congenital defects that alter hearing or vision in children born in the city of Bogotá between 2002 and 2016

Q4Q2Caso clínico1-7Introduction: Congenital defects affecting the auditory and visual capacity of newborns represent a public health problem as they result in substantial disability, directly impacting the quality of life of newborns and their families. Objective: To evaluate risk factors associated with congenital defects that alter hearing or vision in newborns in the city of Bogotá between 2002 and 2016. Method: Data from the Bogotá Birth Defects Surveillance and Follow-up Program was used, which consolidated data regarding 167 ECLAMC study (Estudio Colaborativo Latino Americano de Malformaciones Congénitas, in spanish) variables in a case-control design to identify risk factors for birth defects after parents provided signed informed consent. Cases were defined as any newborn (alive or stillborn) with a weight greater than 500 g with any visual or hearing abnormality. Controls were defined as newborn in the same hospital and month with no birth defects. Groups were formed according to the case presentation as follows: isolated eye anomaly, isolated ear anomaly, polymalformative, syndromic, and teratogenic. Results: In total, 402,657 births were reviewed, of which 968 cases had some congenital defects that alter hearing or vision. An association was found between the presence of defects and prematurity, as well as between syndromic cases and increasing maternal age. When comparing cases and controls with the risk of having a birth defect, multiparity had an odds ratio (OR) of 1.47 (95% CI: 1.27–1.71), acute respiratory infection had an OR of 2.41 (95% CI: 1.04–5.58), low maternal education level had an OR of 1.34 (95% CI:1.10–1.62), low paternal education had an OR of 1.42, (95% CI:1.17–1.73), manual labor in the maternal occupation had an OR of 1.31 (95% CI:1.03–1.67), and a history of congenital anomalies in the family had an OR of 1.55 (95% CI:1.19–2.00). Conclusion: This research allowed the identification of epidemiological data and significant risk factors for congenital defects that alter hearing or vision in the population of Bogotá