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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12881-015-0149-2) contains supplementary material, which is available to authorized users

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

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

Antecedentes: la detección de anomalías cromosómicas es fundamental en diversas áreas médicas; para diagnosticar defectos de nacimiento, trastornos genéticos e infertilidad, entre otros fenotipos complejos, en personas de una amplia gama de edades. De ahí que el presente estudio quiera contribuir al conocimiento del tipo y frecuencia de alteraciones cromosómicas y polimorfismos en Ecuador. Métodos: Se fusionaron y analizaron registros citogenéticos de diferentes provincias ecuatorianas para construir un registro nacional de acceso abierto de alteraciones cromosómicas y polimorfismos. Resultados: De 28.806 cariotipos analizados, 6.008 (20,9%) presentaron alteraciones. El síndrome de Down fue la alteración autosómica más frecuente (88,28%), seguido del síndrome de Turner (60,50%), una aneuploidía gonosómica. Un alto porcentaje recurrente de mosaicismo del síndrome de Down (7,45%) informado aquí, así como por los registros preliminares ecuatorianos anteriores, podría estar asociado con la ubicación geográfica y la composición ancestral mixta. Las translocaciones (2,46%) y polimorfismos (7,84%) no fueron tan numerosos como las autosomopatías (64,33%) y las gonosomopatías (25,37%). Como complemento a las pruebas citogenéticas convencionales, las herramientas moleculares han permitido identificar regiones de alteraciones submicroscópicas o genes candidatos que posiblemente puedan estar implicados en los síntomas y fenotipos de los pacientes. Conclusión: El Registro Nacional Ecuatoriano de Alteraciones y Polimorfismos Cromosómicos proporciona una línea de base para comprender mejor las anomalías cromosómicas en el Ecuador y por ende su manejo clínico y conocimiento.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

Comprehensive Analysis Via Exome Sequencing Uncovers Genetic Etiology In Autosomal Recessive Non-Syndromic Deafness In A Large Multiethnic Cohort

Purpose Autosomal recessive non-syndromic 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.PubMedWoSScopu

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

Abstract 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