RESUMEN
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.
Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Humanos , Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Fenotipo , SíndromeRESUMEN
BACKGROUND AND OBJECTIVE: Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumor in children and a potential cause of blindness from therapeutic eye ablation, second tumors in germ line mutation carriers, and even death when untreated. The molecular scanning of RB1 in search of germ line mutations in 213 retinoblastoma patients from Spain, Cuba, Colombia and Serbia, has led to the detection of 106 mutations whose knowledge is important for genetic counselling and characterization of phenotypic-genotypic relations. PATIENTS AND METHOD: Mutational study (PCR-sequentiation and microsatellites analysis) in patients with retinoblastoma, from Spain, Cuba, Colombia and Serbia. RESULTS: 45% of mutations, including most of the frame shift (FS), missense (MS) and splicing (SP), were new, while all nonsense mutations (NS) corresponded to hypermutable sites in RB1. Germ line mutations were found in 22% of unilateral sporadic patients. The incidence of SP plus MS mutations in this group of patients was greater (p = 0.018) than in bilateral patients. The frequency of SP mutations was higher (p = 0.0003) in Spain and France than in Germany and United Kingdom, while the incidence of NS mutations was lower (p = 0.0006). SP mutations were associated with the low penetrance phenotype and were also overrepresented (p = 0.018) in patients with delayed retinoblastoma onset. CONCLUSIONS: Mutational scanning of unilateral patients is important for genetic counselling and may help decipher the molecular mechanisms leading to low penetrance or expressivity. The functional characterization of mutations associated with low-penetrance or expressivity phenotypes and the molecular classification of tumors using multiple expression profiling is important for a better understanding of the retinoblastoma pathogenesis.
Asunto(s)
Asesoramiento Genético , Mutación , Proteína de Retinoblastoma/genética , Retinoblastoma/epidemiología , Retinoblastoma/genética , Niño , Preescolar , Femenino , Humanos , Masculino , LinajeRESUMEN
Fundamento y objetivo: El retinoblastoma, prototipo de cáncer hereditario, puede causar ceguera, por enucleación terapéutica, segundos tumores en pacientes con mutación germinal e incluso muerte si no se trata. El diagnóstico molecular de 213 pacientes a lo largo de 5 años ha conducido a la detección de 106 mutaciones que se analizan desde la perspectiva de la epidemiología molecular y consejo genético. Pacientes y método: Estudio mutacional (reacción en cadena de la polimerasa, secuenciación y análisis de microsatélites) en pacientes con retinoblastoma procedentes de España, Cuba, Colombia y Serbia. Resultados: Un 45% de las mutaciones analizadas son nuevas y corresponden a mutaciones de tipo de corrimiento de pauta de lectura, cambio de aminoácido o procesado del ácido ribonucleico. Todas las mutaciones sin sentido corresponden a sitios de alta mutabilidad. La tasa de detección de mutaciones en pacientes unilaterales esporádicos es alta (22%). En este grupo de pacientes se detecta una mayor incidencia (p = 0,018) de mutaciones de cambio de aminoácido y procesamiento. España y Francia muestran una incidencia mayor de mutaciones del procesado (p = 0,0003) que Alemania y el Reino Unido, países en los que predominan las mutaciones sin sentido (p = 0,0006). Las mutaciones del procesado se asocian al fenotipo de baja penetración y retraso en la aparición de tumores (p = 0,018). Conclusiones: La incidencia de mutaciones germinales en pacientes unilaterales y las relaciones fenotipo/genotipo analizadas indican la necesidad del consejo genético basado en el diagnóstico molecular temprano. La mejora de las técnicas diagnósticas, la caracterización funcional de mutaciones asociadas a baja penetrancia o expresividad y el estudio del transcriptoma de los tumores son objetivos necesarios para definir mejor la patogenia del retinoblastoma
Background and objective: Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumor in children and a potential cause of blindness from therapeutic eye ablation, second tumors in germ line mutation carriers, and even death when untreated. The molecular scanning of RB1 in search of germ line mutations in 213 retinoblastoma patients from Spain, Cuba, Colombia and Serbia, has led to the detection of 106 mutations whose knowledge is important for genetic counselling and characterization of phenotypic-genotypic relations. Patients and method: Mutational study (PCR-sequentiation and microsatellites analysis) in patients with retinoblastoma, from Spain, Cuba, Colombia and Serbia. Results: 45% of mutations, including most of the frame shift (FS), missense (MS) and splicing (SP), were new, while all nonsense mutations (NS) corresponded to hypermutable sites in RB1. Germ line mutations were found in 22% of unilateral sporadic patients. The incidence of SP plus MS mutations in this group of patients was greater (p = 0.018) than in bilateral patients. The frequency of SP mutations was higher (p = 0.0003) in Spain and France than in Germany and United Kingdom, while the incidence of NS mutations was lower (p = 0.0006). SP mutations were associated with the low penetrance phenotype and were also overrepresented (p = 0.018) in patients with delayed retinoblastoma onset. Conclusions: Mutational scanning of unilateral patients is important for genetic counselling and may help decipher the molecular mechanisms leading to low penetrance or expressivity. The functional characterization of mutations associated with low-penetrance or expressivity phenotypes and the molecular classification of tumors using multiple expression profiling is important for a better understanding of the retinoblastoma pathogenesis
Asunto(s)
Humanos , Retinoblastoma/diagnóstico , Epidemiología Molecular/métodos , Neoplasias de la Retina/genética , Retinoblastoma/genética , Genes de Retinoblastoma/genética , Técnicas de Diagnóstico Molecular/métodos , Asesoramiento Genético/métodos , Mutación/genéticaRESUMEN
Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.
Asunto(s)
Mutación , Proteína de Retinoblastoma/genética , Retinoblastoma/genética , Colombia , Cuba , Análisis Mutacional de ADN , Exones , Genes de Retinoblastoma , Genotipo , Humanos , Mutación Missense , Fenotipo , Empalme del ARN/genética , EspañaRESUMEN
We report five patients from two different pedigrees with the ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC). All had features of ectodermal dysplasia, but only three had limb ectrodactyly and orofacial clefting. The present patients illustrate the great phenotypic variability in the EEC syndrome. As no single feature, including any of the three cardinal signs, is mandatory for syndrome diagnosis, a meticulous examination of all family members is needed.