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1.
Am J Hum Genet ; 99(6): 1368-1376, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27889060

RESUMEN

Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.


Asunto(s)
Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Epilepsia/complicaciones , Epilepsia/genética , Genes Recesivos/genética , Mutación , Atrofia Óptica/complicaciones , Atrofia Óptica/genética , Edad de Inicio , Niño , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Microcefalia/genética , Linaje , Síndrome
2.
J Med Genet ; 52(1): 61-70, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25411445

RESUMEN

BACKGROUND: Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling. METHODS: By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX. RESULTS: We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate. CONCLUSIONS: Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.


Asunto(s)
Oxidorreductasas/genética , Fenotipo , Espasmos Infantiles/genética , Ataxias Espinocerebelosas/genética , Proteínas Supresoras de Tumor/genética , Codón sin Sentido/genética , Hibridación Genómica Comparativa , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación Missense/genética , Espasmos Infantiles/patología , Ataxias Espinocerebelosas/patología , Oxidorreductasa que Contiene Dominios WW
3.
Eur J Hum Genet ; 20(12): 1216-23, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22739344

RESUMEN

The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to-6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.


Asunto(s)
Cromosomas Humanos Par 14/genética , Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Proteínas del Tejido Nervioso/genética , Elementos Silenciadores Transcripcionales/genética , Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/genética , Línea Celular , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Discinesias/diagnóstico , Discinesias/genética , Femenino , Factores de Transcripción Forkhead/metabolismo , Eliminación de Gen , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Microcefalia/diagnóstico , Proteínas del Tejido Nervioso/metabolismo , Fenotipo , Mapeo Físico de Cromosoma , Mutación Puntual , Proteína Quinasa C/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome , Transcripción Genética
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