RESUMEN
We describe a 22-year-old woman with a de novo paracentric inversion of the long arm of chromosome 14 with breakpoints at q13 and q24 and associated with epilepsy, dysarthria and severe incapacitating involuntary movements present since birth. These movements were incessant when awake but absent when asleep. She had unusual facies with downward slant of palpebral fissures, epicanthi, broad philtral groove, flat malar region, large, cup shaped and low-set ears, and short neck. Her decidual and permanent dentition lacked all premolars and molars. Psychological assessment at ages 6 and 15 years showed mild mental retardation. In spite of the aggravation of the neurological symptoms no decline of mental capacity was observed. A brain MRI was normal at 19 years of age. Early on EEG showed changes compatible with partial epilepsy, and at later stages there was, contrary to expectation, only a mild background slowing. Urinary metabolic screening tests and a search for vacuolated lymphocytes were negative. Previously, four cases with a similar inversion have been described. Of these, three were familial with normal phenotype, and the fourth was de novo with severe mental retardation, microcephaly and involuntary movements. Our case is the second de novo inversion of the long arm of chromosome 14 with breakpoints at q13 and q24. The observations in the two patients suggest that this chromosomal rearrangement is associated with a congenital complex movement disorder.
Asunto(s)
Inversión Cromosómica/genética , Cromosomas Humanos Par 14/genética , Epilepsia/complicaciones , Epilepsia/genética , Cara/anomalías , Trastornos del Movimiento/complicaciones , Trastornos del Movimiento/genética , Anomalías Múltiples/genética , Adulto , Encéfalo/anatomía & histología , Rotura Cromosómica/genética , Electroencefalografía , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Leucopenia/genética , Imagen por Resonancia Magnética , Mutación Puntual/genética , Aberraciones Cromosómicas Sexuales , Anomalías Dentarias/genéticaRESUMEN
We determined the genomic organization of the human OPA-containing gene (HOPA) and characterized its developmental expression. The gene encoding HOPA, which contains a rare polymorphism tightly associated with non-specific mental retardation, is 25 kb in length and consists of 44 exons. A promoter scan analysis demonstrates two possible transcription initiation sites without TATA boxes upstream from the putative translation initiation start site. Several informative polymorphisms are evident in the sequence including a large pentanucleotide repeat. Northern blot analysis of the gene transcript and its murine orthologue, MOPA-1, demonstrates that only one transcript is expressed throughout the soma and the CNS, and that the transcript is highly expressed during early fetal development. We conclude that the delineation of the function of the HOPA gene locus merits further study.
Asunto(s)
Cromosoma X , Northern Blotting , Encéfalo/metabolismo , Cósmidos , ADN Complementario/análisis , Embrión de Mamíferos/metabolismo , Genotipo , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Polimorfismo Genético , Análisis de Secuencia de ADN , Síndrome , Distribución TisularRESUMEN
Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<< 1% in non-iII males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.
Asunto(s)
Elementos Transponibles de ADN , Variación Genética , Discapacidad Intelectual/genética , Polimorfismo Genético , Cromosoma X , Alelos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , California/epidemiología , Mapeo Cromosómico , Secuencia Conservada , Cósmidos , Europa (Continente)/epidemiología , Exones , Femenino , Finlandia/epidemiología , Síndrome del Cromosoma X Frágil/genética , Biblioteca de Genes , Humanos , Hipotiroidismo/epidemiología , Hipotiroidismo/genética , Hibridación Fluorescente in Situ , Masculino , Ratones , Datos de Secuencia Molecular , Prevalencia , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Repeticiones de TrinucleótidosRESUMEN
The frequencies of folate-sensitive autosomal rare fragile sites (ARFS) were compared in populations of mentally retarded, mentally subnormal, and mentally normal children and of patients referred for diagnostic chromosome study. The frequencies did not differ significantly. Altogether, an autosomal rare fragile site was found in 16 of 1,445 individuals (1 in 90). Of six different folate-sensitive ARFS detected, the most common one was FRA9A, with a frequency of 1 in 241 individuals. In addition, FRA17A, classified as a distamycin A-inducible fragile site, was found with a frequency of 1 in 206. It was regarded as a spontaneously expressive fragile site. In 19 families in which transmission of an autosomal rare fragile site was studied, the mother was the carrier in 16 families and the father, in one family. The mean percentage (+/- SD) of cells expressing ARFS in 55 individuals was 19% (+/- 11.4). The age did not affect the rate of expression. When the rate of expression was calculated separately in a group of mentally retarded (mean = 23.4%) and in a group of mentally normal individuals (mean = 16.0%), the difference was statistically significant.
Asunto(s)
Fragilidad Cromosómica , Bandeo Cromosómico , Sitios Frágiles del Cromosoma , Mapeo Cromosómico , Ácido Fólico , Frecuencia de los Genes , Genética de Población , Humanos , Discapacidad Intelectual/genética , Linaje , Translocación GenéticaRESUMEN
A boy with several dysmorphic features and suffering from mental and motor retardation was found to have a de novo interstitial deletion of chromosome 15, involving bands q13 to q15. His clinical picture is described and compared with the clinical features reported in other deletions of this chromosome, located or extending distally from the region associated with Prader-Willi syndrome.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15/ultraestructura , Síndrome de Prader-Willi/genética , Niño , Mapeo Cromosómico , Humanos , Cariotipificación , MasculinoRESUMEN
Eighty-five mentally retarded patients had their chromosomes examined by using the high resolution banding techniques. Fifty-nine of them had multiple congenital anomalies and/or dysmorphic features. Twenty-six had mental retardation but no major anomalies; they were primarily suspected of having the fragile X syndrome. This suspicion was first excluded. Fifteen patients were found to have a chromosome aberration, interpreted as clinically significant. Eleven of them had been examined earlier by conventional methods. The aberrations found were divided into three groups: (I) those detectable with an accuracy of ca. 300-400 bands (N = 4), (II) those detectable with an accuracy of ca. 400-550 bands (N = 6) and (III) those detectable with an accuracy of ca. 550-850 bands (N = 5). The aberrations are described and discussed.
Asunto(s)
Aberraciones Cromosómicas , Discapacidad Intelectual/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Bandeo Cromosómico , Femenino , Humanos , Lactante , Masculino , Persona de Mediana EdadRESUMEN
High resolution chromosome banding showed a male infant with profound mental retardation, hypertonia and multiple congenital anomalies to have the karyotype 46,XY,-der (2),t(2;12)(q37.3;q24.13)pat. Most of the clinical findings were compatible with those of the previously described cases with partial trisomy 12q. Some of the clinical features seem to disappear with increasing age.