Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort.

PURPOSE: Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). METHODS: After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes. RESULTS: We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects. CONCLUSION: We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371.

Novel domain-specific POU3F4 mutations are associated with X-linked deafness: examples from different populations.

BACKGROUND: Mutations in the POU3F4 gene cause X-linked deafness type 3 (DFN3), which is characterized by inner ear anomalies. METHODS: Three Turkish, one Ecuadorian, and one Nigerian families were included based on either inner ear anomalies detected in probands or X-linked family histories. Exome sequencing and/or Sanger sequencing were performed in order to identify the causative DNA variants in these families. RESULTS: Four novel, c.707A>C (p.(Glu236Ala)), c.772delG (p.(Glu258ArgfsX30)), c.902C>T (p.(Pro301Leu)), c.987T>C (p.(Ile308Thr)), and one previously reported mutation c.346delG (p.(Ala116ProfsX26)) in POU3F4, were identified. All mutations identified are predicted to affect the POU-specific or POU homeo domains of the protein and co-segregated with deafness in all families. CONCLUSIONS: Expanding the spectrum of POU3F4 mutations in different populations along with their associated phenotypes provides better understanding of their clinical importance and will be helpful in clinical evaluation and counseling of the affected individuals.

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.

Association between the APOE ε4 Allele and Late-Onset Alzheimer's Disease in an Ecuadorian Mestizo Population.

Alzheimer's disease (AD) is the most common neurodegenerative disease. It has two main pathological hallmarks: amyloid plaques and neurofibrillary tangles. The APOE ε4 allele has been recognized as the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) in several populations worldwide, yet the risk varies by region and ethnicity. The aims of this study were to describe APOE allele and genotype frequencies and examine the relationship between the APOE ε4 allele and LOAD risk in an Ecuadorian Mestizo population. We carried out a case-control study comprising 56 individuals clinically diagnosed with probable AD (≥65 years of age) and 58 unrelated healthy control subjects (≥65 years of age). Genotyping was performed using the real-time PCR method. Our data showed that allelic and genotypic frequencies follow the trends observed in most worldwide populations. We also found a high-risk association between APOE ε4 allele carriers and LOAD (OR = 7.286; 95% CI = 2.824-18.799; p < 0.001). Therefore, we concluded that APOE ε4 must be considered an important genetic risk factor for LOAD in the Ecuadorian Mestizo population. Additionally, we suggest that in mixed populations the effects of admixture and ethnic identity should be differentiated when evaluating genetic contributions to Alzheimer's disease risk.

La importancia de un diagnóstico clínico temprano en la distrofia muscular de Duchenne: mutaciones encontradas en siete pacientes ecuatorianos / The importance of early clinical diagnosis in Duchenne muscular dystrophy: mutations found in seven Ecuadorian patients

Duchenne muscular dystrophy (DMD) is a recessive X-linked genetic disease caused by mutations in the dystrophin gene. In Ecuador, the procedure to diagnose this disease is not standardized by the public health system. The aim of this study was to propose an algorithm for DMD diagnosis in order to establish a standard protocol, emphasize early diagnosis and identify pathological mutations in affected patients. Subjects and methods We reported seven Ecuadorian male patients with clinical signs of DMD. They were evaluated by pediatricians, neurologists and geneticists, who made a medical record considering age of onset, pedigree, symptoms, serum CK levels and EMG analysis results. The confrmatory diagnosis and the type of mutations were identifed by molecular genetic testing. Results The most common symptoms reported from patients were frequent falls, unstable gait, diminished muscular strength, calf pseudohypertrophy and diffculty climbing stairs. Moreover, two types of mutations in DMD gene were found, duplications and deletions. The effects of mutations in the reading frame were out-of frame for all patients, except for one, whose mutations showed an in-frame effect on the gene. Conclusions It is important to emphasize the timely diagnosis of DMD to reduce the appearance of new cases, as well as the emotional impact on families. When there is a suspicion of a neuromuscular condition in male children, we recommend following the proposed algorithm in order to offer an early and effcient DMD diagnosis, confrm the disease and to provide an appropriate genetic counseling to patients and their families

La Distrofa Muscular de Duchenne (DMD) es una enfermedad genética recesiva ligada al cromosoma X, causada por mutaciones en el gen de la distrofna. En Ecuador, el procedimiento para diagnosticar esta enfermedad no ha sido estandarizado por el Sistema de Salud Pública. El objetivo de este estudio fue proponer un algoritmo para el diagnóstico de DMD con el fn de establecer un protocolo estándar, enfatizar el diagnóstico temprano e identifcar las mutaciones patológicas en los pacientes afectados. Sujetos y métodos Se reportaron siete pacientes ecuatorianos masculinos con signos clínicos de DMD. Estos fueron evaluados por pediatras, neurólogos y genetistas, quienes elaboraron una historia clínica incluyendo datos de la edad de inicio, árbol genealógico, síntomas, resultados de los niveles de CK en suero y el análisis del EMG. El diagnóstico confrmatorio de DMD y el tipo de mutaciones fueron identifcados con pruebas genéticas moleculares. Resultados Los síntomas más comunes reportados en los pacientes fueron caídas frecuentes, inestabilidad en la marcha, disminución de la fuerza muscular, pseudo-hipertrofa de pantorrillas y difcultad para subir escaleras. Además, dos tipos de mutaciones fueron halladas en el gen DMD: duplicaciones y deleciones. Los efectos de las mutaciones en el marco de lectura del gen de la distrofna fueron out-frame para todos los pacientes, excepto en uno, cuyas mutaciones tuvieron un efecto in-frame sobre el gen. Conclusiones Enfatizar en el diagnóstico temprano de DMD es importante para reducir la aparición de nuevos casos, así como el impacto emocional en las familias. Cuando existe la sospecha de una enfermedad neuromuscular en niños, recomendamos seguir el algoritmo propuesto con el fn de ofrecer un diagnóstico oportuno y efciente, confrmar el diagnóstico de la enfermedad y proveer el asesoramiento genético apropiado a los pacientes y sus familiares