Micropene e hipospadias distal debido a variante patogénica en NR5A1 no descrita previamente en la literatura / Micropenis and distal hypospadias due to a pathogenic variant in NR5A1 not previously reported in the literatura

INTRODUCCIÓN: El factor de esteroidogénesis 1 (SF-1), codificado por el gen NR5A1, juega un papel fundamental en el desarrollo de la glándula adrenal, de la función reproductiva, del bazo y del hipotálamo medial. Su alteración, fundamentalmente por variantes patogénicas en heterocigosis, se relaciona con desórdenes en el desarrollo y diferenciación sexual. Aunque puede afectar a ambos sexos, las mutaciones se han descrito principalmente en varones con hipospadias, micropene, criptorquidia, infertilidad y/o anorquia. CASO CLÍNICO: Paciente de 13 años con hipospadias y micropene en el que se ha identificado el cambio p.Ser203Ile en heterocigosis en el gen NR5A1, que no ha sido descrito previamente en la literatura. DISCUSIÓN: El espectro clínico de las variantes patogénicas del gen NR5A1 que alteran la proteína SF-1 es heterogéneo, pudiendo asociar, en el caso de los varones, alteraciones en el desarrollo y descenso testicular, en la esteroidogénesis, en la función adrenal y anomalías esplénicas. En nuestro paciente, las anomalías consisten en micropene e hipospadias pero las gónadas se sitúan en posición escrotal, los valores de testosterona son adecuados al desarrollo puberal, los valores de ACTH y cortisol están dentro de la normalidad y la ecografía abdominal no muestra anomalías del bazo. Este tipo de alteraciones genéticas deben tenerse en cuenta en varones con micropene, hipospadias y criptorquidia. En el caso de confirmarse, se debe hacer un cribado y seguimiento del resto de alteraciones que pueden asociarse

INTRODUCTION: The steroidogenesis factor 1 (SF-1), encoded by the NR5A1 gene, plays a fundamental role in the development of the adrenal gland, reproductive function, spleen and medial hypothalamus. Its alteration, mainly due to mutations in heterozygosis, is related to disorders of sex development. Although it can affect both sexes, mutations have been described mainly in males with hypospadias, micropenis, cryptorchidism, infertility and/or anorchia. CASE REPORT: A 13-year-old patient with hypospadias and micropenis in whom p.Ser203Ile change was identified in heterozygosis in the NR5A1 gene, which has not been previously described in the literature. DISCUSSION: The clinical spectrum of the mutation of the SF-1 gene is heterogeneous, being able to associate, in the case of male patients, alterations in the development and testicular descent, in the steroidogenesis, in the adrenal function and splenic anomalies. In our patient, the anomalies consist of micropenis and hypospadias but the gonads are placed in the scrotal position, the testosterone values are adequate for pubertal development, the values of ACTH and cortisol are within normal and the abdominal ultrasound does not show splenic anomalies. This type of genetic alterations should be taken into account in males affected by micropenis, hypospadias and cryptorchidism. In the case of confirmation, a screening and monitoring of the rest of the alterations that can be associated should be done

Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.

Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range.

Functional analysis of splicing mutations in MYO7A and USH2A genes.

Usher syndrome is defined by the association of sensorineural hearing loss, retinitis pigmentosa and variable vestibular dysfunction. Many disease-causative mutations have been identified in MYO7A and USH2A genes, which play a major role in Usher syndrome type I and type II, respectively. The pathogenic nature of mutations that lead to premature stop codons is not questioned; nevertheless, additional studies are needed to verify the pathogenicity of some changes such as those putatively involved in the splice process. Five putative splice-site variants were detected in our cohort of patients: c.2283-1G>T and c.5856G>A in MYO7A and c.1841-2A>G, c.2167+5G>A and c.5298+1G>C in the USH2A gene. In this study, we analyze these changes with bioinformatic tools and investigate the expression of MYO7A and USH2A transcripts through hybrid minigene assays. Our study showed that all five mutations abolished the consensus splice site producing the skipping of involved exons. In addition, for variant c.2167+5G>A, a new donor splice site was observed. Our data reveal the pathogenic nature of the analyzed variants. The fact that splicing mutations led to in-frame or out-of-frame alterations cannot explain phenotypic differences, thus, genotype-phenotype correlations cannot be inferred.

[Genetic counselling in visual and auditory disorders]. / El asesoramiento genético en los déficits visuales y auditivos.

PURPOSE: Inherited retinal dystrophies and hearing loss disorders have a broad clinical and genetic heterogeneity. Over the last decade there have been major advances in our understanding of the molecular pathology of these diseases; currently over 200 genes and loci are known to be involved in retinal disorders, and over 60 genes/loci are causative for hearing impairment. METHODS: Genetic testing is crucial for confirming the diagnosis at a molecular level. It also allows a more precise prognosis to be made of the future clinical evolution, as well as an accurate genetic and reproductive counselling, and raises the possibility of creating genetically homogeneous groups of patients for future clinical trials. RESULTS: The high number of genes responsible for these disorders makes molecular testing overwhelming in terms of cost, time and technical effectiveness, and no centre offers testing of all known genes. Several diagnostic tools have emerged recently to circumvent this problem. CONCLUSIONS: In this report, we review the vast genetic heterogeneity of retinal dystrophies and hypoacusis, recent advances in gene discovery, the different DNA-based microarray technologies available for molecular testing, their benefits and limitations, and novel therapeutic approaches.

El asesoramiento genético en los déficits visuales y auditivos / Genetic counselling in visual and auditory disorders

Objetivo: Las enfermedades hereditarias que afectana la retina y la audición presentan una ampliaheterogeneidad clínica y genética. Durante la pasadadécada se han producido importantes avances en elconocimiento de la patogenia molecular de estasenfermedades y, actualmente, más de 200 genes yloci están implicados en enfermedades de la retina ymás de 60 son responsables de pérdida de audición.Método: El estudio genético molecular es crucialpara confirmar el diagnóstico clínico, permite, en ocasiones,conocer el pronóstico de la enfermedad, unconsejo genético y reproductivo adecuado y permitela posibilidad de crear grupos de pacientes genéticamentehomogéneos para futuros ensayos clínicos.Resultados: El elevado número de genes implicadoshace que el diagnóstico molecular no sea factibleen términos de coste, tiempo y esfuerzo técnicoy no existe ningún centro que oferte el análisis detodos los genes conocidos. Recientemente, se handesarrollado varias herramientas diagnósticas dirigidasa paliar este problema. Conclusiones: En este trabajo se ha revisado laamplia heterogeneidad genética de las distrofiasretinianas y la hipoacusia, los recientes descubrimientosde nuevos genes, las distintas herramientasdiagnósticas basadas en microchips de ADN, susventajas y limitaciones y los nuevos avances en buscade una terapia

Purpose: Inherited retinal dystrophies and hearingloss disorders have a broad clinical and geneticheterogeneity. Over the last decade there have beenmajor advances in our understanding of the molecularpathology of these diseases; currently over 200genes and loci are known to be involved in retinaldisorders, and over 60 genes/loci are causative forhearing impairment.Methods: Genetic testing is crucial for confirmingthe diagnosis at a molecular level. It also allows amore precise prognosis to be made of the future clinicalevolution, as well as an accurate genetic andreproductive counselling, and raises the possibilityof creating genetically homogeneous groups ofpatients for future clinical trials.Results: The high number of genes responsible forthese disorders makes molecular testing overwhelmingin terms of cost, time and technical effectiveness,and no centre offers testing of all knowngenes. Several diagnostic tools have emergedrecently to circumvent this problem. Conclusions: In this report, we review the vastgenetic heterogeneity of retinal dystrophies andhypoacusis, recent advances in gene discovery, thedifferent DNA-based microarray technologies availablefor molecular testing, their benefits and limitations, and novel therapeutic approaches

Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I.

Mutations in the human gene encoding cadherin23 (CDH23) cause Usher syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher syndrome type I have CDH23 mutations.

Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II.

Mutations in USH2A gene have been shown to be responsible for Usher syndrome type II, an autosomal recessive disorder characterised by hearing loss and retinitis pigmentosa. USH2A was firstly described as consisting of 21 exons, but 52 novel exons at the 3' end of the gene were recently identified. In this report, a mutation analysis of the new 52 exons of USH2A gene was carried out in 32 unrelated patients in which both disease-causing mutations could not be found after the screening of the first 21 exons of the USH2A gene. On analysing the new 52 exons, fourteen novel mutations were identified in 14 out of the 32 cases studied, including 7 missense, 5 frameshift, 1 duplication and a putative splice-site mutation.

Mutation profile of the MYO7A gene in Spanish patients with Usher syndrome type I.

Usher syndrome type I is the most severe form of Usher syndrome. It is an autosomal recessive disorder characterized by profound congenital sensorineural deafness, retinitis pigmentosa, and vestibular abnormalities. Mutations in the myosin VIIA gene (MYO7A) are responsible for Usher syndrome type 1B (USH1B). This gene is thought to bear greatest responsibility for USH1 and, depending on the study, has been reported to account for between 24% and 59% of USH1 cases. In this report a mutation screening of the MYO7A gene was carried out in a series of 48 unrelated USH1 families using single strand conformation polymorphism analysis (SSCP) and direct sequencing of those fragments showed an abnormal electrophoretic pattern. Twenty-five mutations were identified in 23 out of the 48 families studied (47.9%). Twelve of these mutations were novel, including five missense mutations, three premature stop codons, three frameshift, and one putative splice-site mutation. Based on our results we can conclude there is an absence of hot spot mutations in the MYO7A gene and that this gene plays a major role in Usher syndrome.

[Molecular genetic study of Usher syndrome in Spain]. / Estudio genético molecular del síndrome de Usher en España.

Usher syndrome (USH) associates deafness and retinitis pigmentosa (RP). It is a disease both clinically and genetically heterogeneous. It is inherited as an autosomal recessive trait and its prevalence makes it the most frequent association of hearing loss and RP. Clinically Usher syndrome is divided into type I (USH1), II (USH2) and III (USH3), according to the severity of hearing loss, age of onset of RP and the existence or not of vestibular dysfunction. There are at least 7 different localizations for USH1 and 5 genes have been identified. For USH2, 3 loci and 2 genes have been reported and USH3 is due to Clarin-1 gene. Our aim is to perform a clinical and genetic characterization of all Usher syndrome patients in Spain.

Estudio genético molecular del síndrome de Usher en España / Molecular genetic study of Usher syndrome in Spain

El síndrome de Usher (USH) asocia sordera y retinosis pigmentaria (RP). Es una enfermedad heterogénea tanto clínica como genéticamente. Su modo de transmisión es autosómico recesivo y su prevalencia la convierte en la asociación de sordera y ceguera de origen genético más frecuente. Clínicamente, el síndrome de Usher se divide en los tipos I (USH1), II (USH2) y III (USH3) en función de la gravedad de la sordera, la edad de aparición de la RP y la presencia o no de disfunción vestibular. Existen al menos 7 localizaciones distintas para el USH1 y se han aislado 5 genes responsables de la enfermedad. Respecto al USH2 se han localizado 3 loci y se han aislado dos genes. El USH3 está causado por el gen clarina-1. Nuestro objetivo es la caracterización clínica y genética de los pacientes con síndrome de Usher en España mediante la búsqueda de mutaciones en los genes implicados en la enfermedad y la correlación con el fenotipo

Usher syndrome (USH) associates deafness and retinitis pigmentosa (RP). It is a disease both clinically and genetically heterogeneous. It is inherited as an autosomal recessive trait and its prevalence makes it the most frequent association of hearing loss and RP. Clinically Usher syndrome is divided into type I (USH1), II (USH2) and III (USH3), according to the severity of hearing loss, age of onset of RP and the existence or not of vestibular dysfunction. There are at least 7 different localizations for USH1 and 5 genes have been identified. For USH2, 3 loci and 2 genes have been reported and USH3 is due to Clarin-1 gene. Our aim is to perform a clinical and genetic characterization of all Usher syndrome patients in Spain

Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability.

Usher syndrome type III is an autosomal recessive disorder clinically characterized by the association of retinitis pigmentosa (RP), variable presence of vestibular dysfunction and progressive hearing loss, being the progression of the hearing impairment the critical parameter classically used to distinguish this form from Usher syndrome type I and Usher syndrome type II. Usher syndrome type III clinical subtype is the rarest form of Usher syndrome in Spain, accounting only for 6% of all Usher syndrome Spanish cases. The gene responsible for Usher syndrome type III is named clarin-1 and it is thought to be involved in hair cell and photoreceptor cell synapses. Here, we report a screening for mutations in clarin-1 gene among our series of Usher syndrome Spanish patients. Clarin-1 has been found to be responsible for the disease in only two families: the first one is a previously reported family homozygous for Y63X mutation and the second one, described here, is homozygous for C40G. This accounts for 1.7% of Usher syndrome Spanish families. It is noticeable that, whereas C40G family is clinically compatible with Usher syndrome type III due to the progression of the hearing loss, Y63X family could be diagnosed as Usher syndrome type I because the hearing impairment is profound and stable. Thus, we consider that the progression of hearing loss is not the definitive key parameter to distinguish Usher syndrome type III from Usher syndrome type I and Usher syndrome type II.