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

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

Molecular studies in the GJB2 gene (Cx26) among a deaf population from Bogotá, Colombia: Results of a screening program

Q4Q297-101Objective: We conducted a pilot screening program to define the prevalence of non-syndromic deafness and establish the frequency of mutations in the GJB2 gene (Cx26) in a population of children with congenital deafness in Bogotá, Colombia. Method: From a cohort of 731 children in 8 institutions for the deaf, we identified 322 (44%) with presumed non-syndromic deafness. These were invited to a more detailed evaluation, but 46 chose not to participate. The remaining 276 individuals received a complete ophthalmological evaluation that was normal in 205 (74.3%) and showed salt and pepper retinopathy in 55 (19.9%) and other ocular abnormalities in 16 (5.8%). A comprehensive medical history, and a detailed physical examination were performed in the 205 children with normal ocular exam. Of these, 93 were found to have acquired deafness and/or associated anomalies and 112 (15.3% of the initial 731 children), non-syndromic deafness. The GJB2 gene was sequenced in these 112 individuals. Results: Based on family history, 59.8% (67/112) of these cases had autosomal recessive non-syndromic sensorineural hearing loss and the remaining 40.2% (45/ 112) were sporadic, without apparent known cause. We identified three mutations in the GJB2 gene: 35delG, S199F, and 167delT, all of which have been previously reported in the literature, the variant M34T, and the polymorphism V27I. S199F was the most frequent mutation (17.9%), followed by 35delG (17.0%) and 167delT (0.4%). The mutations in the GJB2 gene were present in 50.7% of the autosomal recessive group and in 33.3% of the sporadic cases

Transient evoked oto-acoustic emission screening in newborns in Bogotá, Colombia : A retrospective study

Q4Q21752-1755Objective: The aim of this study was to investígate the characteristics and performance of transient evoked oto-acoustic emission (TEOAE) hearing screening in newborns in Colombia, and analyze all possiblc variables and factors affccting thc rcsults. Materials and methods: An obscrvational, dcscriptivc and rctrospcctivc study with bivariatc analysis was pcrformcd. The study population consistcd of 56,822 newborns evaluated at thc prívate institution, PREGEN. TEOAE testing was carried out as a pedialric hearing screening test from December 2003 to March 2012. The database from PREGEN was revised, and the protocol for evalualion included the same screening test performed twice. Demographic characteristics were recorded and the newborn’s background was evaluated. Basic statistics of the qualitative and quantitative variables, and statistical analysis were obtained using the chi-square test. Residís: Of the 56,822 records examined, 0.28% were classed as abnormal, which corresponded to a prevalence of 1 in 350. In the screened newborns, 0.08% had a major abnormality or other clinical condition diagnosed, and 0.29% reported a family history of hearing loss. A prevalence of 6.7 in 10,000 was obtained for microtia, which is similar to the 6.4 in 10,000 previously reported in Colombia (database of the Latin-American Collaborative Study of Congenital Malformations - ECLAMC). Statistical analysis demonstrated an association bctwccn presenting with a major anomaly and a higher frequeney of abnormal rcsults on both TEOAE tests. Conclusions: Newborns in Colombia do not currcntly undergo screening for thc carly detection of hearing impairment. The results from this study suggest TEOAE screening tests, when performed twice, are able to detect hearing abnormalities in newborns. This highlights the need to improve the long-term evaluation and moniloring of patients in Colombia through diagnostic tests, and lo provide tests that are both sensitive and specific. Furthermore, the use of TEOAE screening is justified by the favorable cost: benefit ratio demonstrated in many countries worldwide

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

A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy

Q1Q1Artículo original823-831Hearing impairment (HI) is a highly heterogeneous group of disorders caused by environmental and genetic factors, with a global incidence of about 1 in every 650-1,000 newborns [Morton, 1991; Mehl and Thomson, 2002]. When the onset of the HI takes place before speech acquisition (prelingual HI), it represents a serious handicap for normal communication and social integration. In developed countries, over 60% of all cases result from a genetic cause [Petit et al., 2001]. Nonsyndromic HI (NSHI) encompasses a variety of disorders, the common feature of which is that the hearing deficit is not associated with any other clinical sign (about 70% of all inherited HI). Different patterns of inheritance are observed in NSHI, but autosomal recessive forms are by far the most frequent