RESUMEN
We report on a 2-year-old dysmorphic girl with prenatal and postnatal growth deficiency, cardiopathy, left-sided hydronephrosis due to pyelourethral junction stenosis, frequent respiratory infections and psychomotor retardation, in whom a de novo unbalanced submicroscopic translocation (11q;20q) was detected by subtelomeric multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analyses. Additional fluorescence in situ hybridization studies with locus-specific BAC probes and analyses with microsatellite markers revealed that this translocation resulted in a paternal chromosome 11q terminal deletion of approximately 8.9 Mb and a subtelomeric 20q duplication of approximately 3.7 Mb. A subtelomeric 20q trisomy has only been reported in four cases so far. A subtelomeric 11q deletion has been clinically reported in 18 patients. We review the clinical phenotype of these patients. We suggest that patients with a subterminal (11q24.2/25-qter) deletion may present with features of the well-known phenotype of terminal 11q deletion or Jacobsen syndrome.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 20/genética , Monosomía/genética , Telómero/genética , Trisomía/genética , Adulto , Preescolar , Rotura Cromosómica , Deleción Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Cariotipificación , Masculino , Técnicas de Amplificación de Ácido Nucleico , SíndromeRESUMEN
Fragile sites are specific genomic loci that form gaps, constrictions and breaks on chromosomes exposed to replication stress conditions. In the father of a patient with Beckwith-Wiedemann syndrome and a pure truncation of 18q22-qter, a new aphidicolin-sensitive fragile site on chromosome 18q22.2 (FRA18C) is described. The region in 18q22 appears highly enriched in flexibility islands previously found to be the characteristic of common fragile site regions. The breakpoint was cloned in this patient. The break disrupts the DOK6 gene and was immediately followed by a repetitive telomere motif, (TTAGGG)(n). Using fluorescent in situ hybridisation, the breakpoint in the daughter was found to coincide with the fragile site in the father. The breakpoint region was highly enriched in AT-rich sequences. It is the first report of an aphidicolin-sensitive fragile site that coincides with an in vivo chromosome truncation in the progeny.
Asunto(s)
Afidicolina/farmacología , Rotura Cromosómica/efectos de los fármacos , Sitios Frágiles del Cromosoma/efectos de los fármacos , Sitios Frágiles del Cromosoma/genética , Cromosomas Humanos Par 18/efectos de los fármacos , Cromosomas Humanos Par 18/genética , Secuencia de Bases , Niño , Deleción Cromosómica , Clonación Molecular , Análisis Mutacional de ADN , Padre , Femenino , Humanos , Datos de Secuencia Molecular , Linaje , Secuencias Repetitivas de Ácidos Nucleicos/genéticaRESUMEN
Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI.
Asunto(s)
Epilepsias Mioclónicas/genética , Eliminación de Gen , Proteínas del Tejido Nervioso/genética , Canales de Sodio/genética , Niño , Mapeo Cromosómico , Codón sin Sentido , Análisis Mutacional de ADN , Epilepsias Mioclónicas/diagnóstico , Femenino , Pruebas Genéticas/métodos , Haplotipos , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.1 , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido SimpleRESUMEN
Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 6/genética , Discapacidad Intelectual/genética , Proteína de Unión a TATA-Box/genética , Anomalías Múltiples/genética , Adolescente , Animales , Ansiedad/genética , Enfermedades en Gemelos/genética , Femenino , Humanos , Masculino , Trastornos de la Memoria/genética , Ratones , Linaje , Gemelos Monocigóticos/genéticaRESUMEN
We report on a 3-year-old girl with psychomotor retardation, cardiopathy, strabismus, umbilical hernia, and facial dysmorphism in whom a de novo unbalanced submicroscopic translocation (10p;18q) was found by MLPA (Multiplex Ligation dependent Probe Amplification) and FISH analyses. Additional FISH studies with locus specific RP11 BAC probes and analyses with microsatellites revealed that the translocation resulted in a deletion estimated between 6 and 9 Mb on the maternal chromosome 18 and a subtelomeric 10p duplication of approximately 6.9 Mb. The proband's karyotype is 46,XX.ish der(18) t(10;18)(18pter-->18q23:10p15 --> 10pter). A subterminal duplication of 10p, as well as a subterminal deletion of 18q have been rarely reported so far. The clinical phenotype of this patient is reviewed and discussed.
Asunto(s)
Anomalías Múltiples/genética , Aneuploidia , Deleción Cromosómica , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 18/genética , Discapacidad Intelectual/genética , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Repeticiones de Microsatélite , Técnicas de Amplificación de Ácido Nucleico , Translocación Genética , TrisomíaRESUMEN
Deletions of the 1q telomere have been reported in several studies screening for subtelomeric rearrangements. However, an adequate clinical description is available from only a few patients. We provide a clinical description of a patient with a subtelomeric deletion of chromosome 1q, previously detected by us in a screening study. Comparison of the clinical presentation of our patient with rare cases reported previously provides further evidence for a specific phenotype of 1q patients, including mental retardation, growth retardation, sometimes with prenatal onset, progressive microcephaly, seizures, hand and foot abnormalities and a variety of midline defects, including corpus callosum, cardiac, genital and gastro-esophageal abnormalities. This clinical presentation is reminiscent of that of patients with larger, microscopically visible deletions of chromosome 1q (>3 Mb) characterized by growth and mental retardation, coarse faces with thin upper lip, epilepsy, and variable other anomalies. In addition, the breakpoint region was mapped to a 26 kb region within the RGS7 gene. Among the 17 known genes in the candidate region, are zinc-finger genes. Other members of this gene family have been implicated in different forms of mental retardation.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Discapacidad Intelectual/patología , Telómero/genética , Anomalías Múltiples/patología , Preescolar , Trastornos del Crecimiento/patología , Humanos , Lactante , Cariotipificación , Masculino , Microcefalia/patología , FenotipoRESUMEN
Cryptic unbalanced rearrangements involving chromosome ends are a significant cause of idiopathic mental retardation. The most frequently used technique to screen for these subtle rearrangements is Multiprobe fluorescence in situ hybridization (FISH). As this is a labor-intensive technique, we used microsatellite genotyping to detect possible subtelomeric rearrangements in a study population. Out of the 70 patients we screened, three chromosomal rearrangements were detected: a deletion of marker D2S2986, a deletion of marker D7S594 and a deletion of marker D19S424. However, none of these aberrations appeared to be disease causing.
Asunto(s)
Aberraciones Cromosómicas , Marcadores Genéticos , Pruebas Genéticas , Discapacidad Intelectual/genética , Telómero , Humanos , Repeticiones de Microsatélite , Polimorfismo GenéticoRESUMEN
Subtelomeric rearrangements are responsible for 5% to 10% of cases of unexplained mental retardation. Despite their clinical relevance, methods to screen for these cytogenetically invisible abnormalities on a routine base are scarce. We screened patients with idiopathic mental retardation for subtelomeric aberrations using multiplex ligation-dependent probe amplification (MLPA). This recently developed technique is based on PCR amplification of ligated probes hybridized to chromosome ends. Currently, 41 telomeres can be screened in just two multiplex reactions. Four subtelomeric rearrangements (5.3%) were detected in a group of 75 patients with mild to severe mental retardation in combination with dysmorphic features and/or a familial history of mental retardation: two terminal 1p deletions, a terminal 1q deletion, and a terminal 3p deletion. Deletions could be verified by FISH and marker analysis. In one case the MLPA indicated a terminal 21q deletion due to a 3-bp deletion at the site of the probe, giving a false-positive rate of 1.3%. This study demonstrates that MLPA is a fast and reliable screening method, potentially suitable for use in routine diagnostics.