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Abstract Objective Orphan diseases must be considered a public health concern, underlying country-specific challenges for their accurate and opportune diagnosis, classification and management. Orphan disease registries have not yet been created in South America, a continent having a population of ~ 415 million inhabitants. In Colombia ~ 3 million of patients are affected by rare diseases. The aim of the present study was to establish the first Colombian national registry for rare diseases. The registry was created after the establishment of laws promoting the development of clinical guidelines for diagnosis, management, census and registry of patients suffering rare diseases. Results In total, 13,215 patients were recorded in the Colombian registry. The survey reported 653 rare diseases. The most common diseases were congenital factor VIII deficiency (hemophilia A) (8.5%), myasthenia gravis (6.4%), von Willebrand disease (5.9%), short stature due to growth hormone qualitative anomaly (4.2%), bronchopulmonary dysplasia (3.9%) and cystic fibrosis (3.2%). Although, a marked under-reporting of cases was observed, some pathologies displayed similar behavior to that reported by other initiatives and databases. The data currently available in the registry provides a baseline for improvement regarding local and regional surveys and the start for better understanding rare diseases in Colombia.

Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1% of women. It has been estimated that the cause remains unexplained in >50% cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease's genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations. The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41% of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology. Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability. The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss.

The neuronal ceroid-lipofuscinoses (NCL) is a group of neurodegenerative disorders characterized by epilepsy, visual failure, progressive mental and motor deterioration, myoclonus, dementia and reduced life expectancy. Classically, NCL-affected individuals have been classified into six categories, which have been mainly defined regarding the clinical onset of symptoms. However, some patients cannot be easily included in a specific group because of significant variation in the age of onset and disease progression. Molecular genetics has emerged in recent years as a useful tool for enhancing NCL subtype classification. Fourteen NCL genetic forms (CLN1 to CLN14) have been described to date. The variant late-infantile form of the disease has been linked to CLN5, CLN6, CLN7 (MFSD8) and CLN8 mutations. Despite advances in the diagnosis of neurodegenerative disorders mutations in these genes may cause similar phenotypes, which rends difficult accurate candidate gene selection for direct sequencing. Three siblings who were affected by variant late-infantile NCL are reported in the present study. We used whole-exome sequencing, direct sequencing and in silico approaches to identify the molecular basis of the disease. We identified the novel c.1219T>C (p.Trp407Arg) and c.1361T>C (p.Met454Thr) MFSD8 pathogenic mutations. Our results highlighted next generation sequencing as a novel and powerful methodological approach for the rapid determination of the molecular diagnosis of NCL. They also provide information regarding the phenotypic and molecular spectrum of CLN7 disease.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to actinic pigmentation changes in the skin and increased incidence of skin cancer. In some cases, patients are affected by neurological alterations. XP is caused by mutations in 8 distinct genes (XPA through XPG and XPV). The XP-V (variant) subtype of the disease results from mutations in a gene (XPV, also named POLH) which encodes for Polη, a member of the Y-DNA polymerase family. Although the presence and severity of skin and neurological dysfunctions differ between XP subtypes, there are overlapping clinical features among subtypes such that the sub-type cannot be deduced from the clinical features. In this study, in order to overcome this drawback, we undertook whole-exome sequencing in two XP sibs and their father. We identified a novel homozygous nonsense mutation (c.897T>G, p.Y299X) in POLH which causes the disease. Our results demonstrate that next generation sequencing is a powerful approach to rapid determination of XP genetic etiology.

BACKGROUND: The human condition known as Premature Ovarian Failure (POF) is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10-15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients. METHODOLOGY/PRINCIPAL FINDINGS: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LOD(max) of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1) included within the largest region did not reveal any causal mutations. CONCLUSIONS/SIGNIFICANCE: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function.

Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (∼30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome-protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA.

La agammaglobulinemia ligada al cromosoma X ó Agammaglobulinemia de Bruton es una inmunodeficiencia que se caracteriza por ausencia de algunas inmunoglobulinas séricas, disminución de los linfocitos B tanto en la médula ósea como en la sangre periférica, hipoplasia de tejido linfoide e infecciones a repetición. Su incidencia es de 1:200000 recién nacidos vivos varones y su herencia es recesiva ligada al cromosoma X. Es causada por mutaciones en el gen BTK que codifia la proteína tirosin kinasa de Bruton que participa en el desarrollo de los linfocitos B. Presentamos dos pacientes masculinos con hallazgos clínicos sugestivos de agammaglobulinemia ligada a X, uno de ellos con onicodistrofia. Se realiza estudio molecular en ambos pacientes, se identifican dos mutaciones nuevas en el gen BTK y se descartan mutaciones en el gen SOX9.

La osteoartropatía hipertrófica primaria (Síndrome Touraine-Solente-Gole o Paquidermoperiostosis) es una entidad hereditaria infrecuente caracterizada por hipocratismo digital, hiperqueratosis y periostosis. Tres formas clínicas han sido descritas: 1) Completa, con hiperqueratosis y periostosis, 2) Incompleta, con alteraciones óseas pero sin hiperqueratosis y 3) Frustra, con hiperqueratosis y cambios óseos mínimos. Su incidencia es desconocida, se presenta con mayor frecuencia en hombres y en el 25%-38% de los casos existe historia familiar. Bonthron, en un estudio reciente describió mutaciones causales homocigotas en el gen HPGD, que codifica la proteina 15-hidroxiprostaglandin deshidrogenasa, una enzima involucrada en la degradación de las prostaglandinas. Se considera que la elevación de la prostaglandina E2, secundaria a la alteración de la actividad enzimática de HPGD, contribuye al desarrollo del cuadro clínico. Presentamos el caso clínico de un paciente de 44 años de edad, masculino, con cuadro de 22 años de evolución consistente en crecimiento de las epífisis distales de los huesos largos, hipocratismo digital, hiperqueratosis, cutis verticis gyrata e hiperhidrosis palmoplantar. La madre, un tío materno y dos hermanos muestran hallazgos clínicos compatibles con esta patología. Los demás miembros de la familia presentan hiperhidrosis e hiperqueratosis palmoplantar. La secuenciación de las regiones codificantes del HPGD en el caso índice es negativa para variantes asociadas al fenotipo. Este hallazgo permite plantear la hipótesis acerca de la posible participación de nuevo locus asociado a la patogénesis de la enfermedad, por lo que se inicia un estudio de ligamiento genético en colaboración con la Universidad de Leeds (UK). Presentamos el caso clínico, una revisión de la literatura y las aproximaciones metodológicas en curso que servirán para cartografiar un locus adicional de la enfermedad y un potencial nuevo mecanismo patogénico.