Ignacio Briceño

High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia

In South America, a high proportion of the population is of Hispanic origin with an important representation in Colombia. Since nothing is known about the contribution of BRCA1 and BRCA2 germline mutations to hereditary breast/ovarian cancer in the Hispanic population from Colombia, we conducted the first study of 53 breast/ovarian cancer families from this country. Comprehensive BRCA mutation screening was performed using a range of techniques, including DHPLC, SSCP, and PTT, followed by DNA sequencing analysis. Thirteen deleterious germline mutations (24.5%) were identified in 53 families, comprising eight in BRCA1 and five in BRCA2. The two recurrent BRCA1 mutations, 3450 delCAAG and A1708E, accounted for 100% of all BRCA1 mutations identified in this cohort and the recurrent 3034 delACAA BRCA2 mutation for 40% of all BRCA2 mutations. Haplotype analyses suggested that each of these mutations has arisen from a common ancestor. The prevalence of BRCA1 or BRCA2 mutations was 50% in multiple case breast cancer families, and was 33% for the breast-ovarian cancer families. Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Colombia. The spectrum of mutations differed completely to that previously reported in Hispanic families of predominantly Mexican origin from Southern California [1] suggesting that specific genetic risk assessment strategies for the different Hispanic populations in South America and in the United States need to be developed.

Genetic and other diseases in the pottery of Tumaco‐La Tolita culture in Colombia–Ecuador

The people of Tumaco‐La Tolita culture inhabited the borders of present‐day Colombia and Ecuador. Already extinct by the time of the Spaniards arrival, they left a huge collection of pottery artifacts depicting everyday life; among these, disease representations were frequently crafted. In this article, we present the results of the personal examination of the largest collections of Tumaco‐La Tolita pottery in Colombia and Ecuador; cases of Down syndrome, achondroplasia, mucopolysaccharidosis I H, mucopolysaccharidosis IV, a tumor of the face and a benign tumor in an old woman were found. We believe these to be among the earliest artistic representations of disease.

The p.T191M mutation of the CBS gene is highly prevalent among homocystinuric patients from Spain, Portugal and South America

In this article, one of the novel mutations, c.208_209+ 8del10, was incorrectly given as c.69_70+8del10. It corresponds to patient 64 in Table 4.

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Colombia’s racial crucible: Y chromosome evidence from six admixed communities in the Department of Bolivar

Abstract Objectives: To determine the African, European and Native-American paternal contributions in genetic samples from the Department of Bolivar (Colombia) with the aims of establishing (1) possible population substructures, and (2) the proportion of biological African heritage in admixed populations of European, Amerindian, and African descent. Methods: Y-SNPs were typed in samples from six communities, including Palenque (renowned for its African linguistic and cultural heritage). Results: Findings reveal a high diversity of Y-haplogroups. With the exception of Palenque, the sum of European male lineages uniformly exceeded 57%. In Palenque, African lineages accounted for 57.7% of its chromosomes, with European male lineages constituting a mere 38.5%. In Pinillos, a significant proportion (23.8%) of the chromosomes belongs to the Native American haplogroup Q1a3a*-M3. Genetic differentiation analyses reveal significant divergences in most pairwise comparisons among the Bolivar municipalities, and the same holds between Bolivar and other South American populations. Conclusions: Heterogeneous patterns of admixture reveal a genetic substructure within the Department of Bolivar. On the paternal side, five out of the six communities studied exhibit a predominantly European gene pool. The exception is Palenque, where European input (38%) is more significant than we had expected.

Absence of the BRCA1 del (exons 9-12) mutation in breast/ovarian cancer families outside of Mexican Hispanics

The frequency and spectrum of germ line mutations in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 shows considerable variation by ethnic group. Most genetic epidemiological studies of the BRCA genes have been performed among Caucasian populations [1], with the exception of a few studies involving other ethnic groups, such as Hispanics [2–4], Asians [5, 6], and African Americans [7–9]. In most of these studies only the frequencies of sequence detectable BRCA mutations were reported and large genomic rearrangements including deletions and insertions of one or more exons, which account for 6–15% of all deleterious mutations in these genes have infrequently been considered [10–12]. Most BRCA mutations are unique; however, few recurrent mutations with founder effects have been found in European, Hispanic, American and Asian populations [13]. In a recent study on Hispanic high-risk breast/ovarian cancer families of mainly Mexican descent from South California, Weitzel and colleagues reported the identification of a novel deletion of BRCA1 exons 9 through 12 using multiplex quantitative differential polymerase chain reaction (PCR) analysis. The deletion was detected in 3.8% of families negative for sequence detectable BRCA mutations [14]. The large genomic rearrangement mutation is considered deleterious as it results in loss of critical functional domains as well as premature truncation of the BRCA1 protein. Given the relatively high prevalence of the deletion in this cohort, the authors suggest to include the screening for this mutation in the genetic testing strategy in Hispanic women without sequence detectable BRCA mutations. The spectra of recurrent sequence detectable BRCA mutations, including some with founder effects in a cohort of Hispanic breast/ovarian cancer families of predominantly Mexican descent from the United States and in a cohort from Colombia have previously been shown to differ completely, with different common mutations being identified in the two populations [2, 4]. In order to investigate, whether the novel BRCA1 founder deletion is also specific for Hispanic families of Mexican descent or whether it also occurs in other Hispanic cohorts, we screened 229 cancer Diana Torres and Muhammad U. Rashid contributed equally to this work.

A Colombian Caribbean population study of 16 Y-chromosome STR loci

Allelic frequencies and haplotypic composition of 305 male unrelated individuals from the Caribbean Colombian states of Atlántico, Bolívar, Cesar, Córdoba, Guajira, Magdalena and Sucre, were determined using 16 Y-chromosome STR loci. Two hundred and ninety three (293) haplotypes were identified, of which 283 were unique and the other 10 were found twice or thrice in the Caribbean population tested. Haplotypic diversity surpassed the values obtained in other populations, ranging from 99.66% in the population of Sucre to 99.99% in the population of Córdoba. We also calculated the overall haplotypic diversity (99.97%) and the discrimination power of these haplotypes (96.1%) in these groups. Analysis of molecular variance (AMOVA) for 10 Colombian and Spanish populations (3139 haplotypes) reveals low differentiation between the Colombian populations of mainly European descent and large distance to Afroamerican populations living in Colombia.

Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes

Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting.

Análisis de ADN mitocondrial en una muestra de restos óseos arcaicos del periodo Herrera en la sabana de Bogotá

Introducción. Los restos óseos arcaicos son fuente privilegiada de información biológica y su caracterización genética permite confirmar o descartar filiaciones propuestas por otras aproximaciones científicas. La historia precolombina de los Andes orientales se divide en tres periodos principales: i) un poblamiento temprano por parte de grupos cazadores-recolectores; ii) un periodo intermedio (Herrera) de pueblos con agricultura incipiente, y iii) un periodo tardío de pueblos chibchas, agrícolas y alfareros (agroalfarero). Objetivo. Analizar el ADN mitocondrial de restos óseos del periodo Herrera. Materiales y métodos. Se analizaron 11 individuos pertenecientes al yacimiento arqueológico Madrid 2-41, con una edad aproximada de 2.000 años. Un fragmento (192 pb) del segmento hipervariable I fue amplificado y secuenciado, siguiendo criterios estrictos de autenticidad de ADN arcaico. Las secuencias se compararon con las existentes en bases de datos de Norteamérica y Europa usando herramientas bioinformáticas. Resultados. Todas las secuencias resultaron idénticas y fueron clasificadas como haplogrupo B. Esto puede relacionarse con el tipo de entierro ritual practicado en Madrid 2-41, es decir, probablemente los individuos analizados hagan parte de una familia jerárquicamente importante en la antigua sociedad Herrera. La búsqueda de secuencias homólogas en las bases de datos estadounidense y europea no arrojó coincidencias exactas, aunque existe el reporte de un individuo amazónico de ~4.000 años de antigüedad (Brasil) cuya secuencia coincide con la hallada en Madrid 2-41. Conclusión. Los individuos del yacimiento arqueológico Madrid 2-41 están estrechamente emparentados entre sí por línea materna y presentan una secuencia aparentemente ausente en poblaciones actuales.

HLA antigens in five Amerindian groups (Yuko, Bari, Tunebo, Guane and Paez) of Colombia: results of 'Expedición Humana'.

The serological HLA types (A, B, C and D loci) were studied in five different Indian groups in Colombia. The range of polymorphism was not very restricted in these groups, but there was significant genetic heterogeneity among the five populations in all the HLA loci. The gene frequency data, when converted into a kinship matrix and a two-dimensional eigen vector plot, showed a closer affinity between Bari and Yuko Indians, while Guane, Tunebo and Paez Indians were not only genetically different from the former but also well-differentiated from each other. It seems therefore from this study that geographical proximity may play a greater role than linguistic similarities in the genetic affinities of Colombian Amerindians.