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1.
Hum Mol Genet ; 26(3): 519-526, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28053047

RESUMEN

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.


Asunto(s)
Trastorno Autístico/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Trastorno Autístico/patología , Discapacidades del Desarrollo/fisiopatología , Femenino , Haploinsuficiencia/genética , Humanos , Discapacidad Intelectual/patología , Masculino , Mutación , Mutación Missense , Linaje , Fenotipo , Conformación Proteica , Proteínas Serina-Treonina Quinasas/química , Proteínas Tirosina Quinasas/química , Relación Estructura-Actividad , Quinasas DyrK
2.
Am J Hum Genet ; 98(2): 373-81, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26833328

RESUMEN

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.


Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Mutación , Ubiquitina Tiolesterasa/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Atresia de las Coanas/diagnóstico , Atresia de las Coanas/genética , Discapacidades del Desarrollo/diagnóstico , Femenino , Genes Ligados a X , Pruebas Genéticas , Humanos , Discapacidad Intelectual/diagnóstico , Datos de Secuencia Molecular , Fenotipo , Ubiquitina Tiolesterasa/metabolismo , Inactivación del Cromosoma X , Adulto Joven
3.
Hum Mutat ; 39(9): 1226-1237, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29897170

RESUMEN

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.


Asunto(s)
Anomalías Múltiples/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Factores de Transcripción NFI/genética , Síndrome de Sotos/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/fisiopatología , Niño , Preescolar , Deleción Cromosómica , Hipotiroidismo Congénito/fisiopatología , Anomalías Craneofaciales/fisiopatología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Exones/genética , Femenino , Deformidades Congénitas de la Mano/fisiopatología , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatología , Mutación Missense/genética , Fenotipo , Displasia Septo-Óptica/genética , Displasia Septo-Óptica/fisiopatología , Síndrome de Sotos/fisiopatología , Adulto Joven
4.
Am J Med Genet A ; 176(5): 1108-1114, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29383814

RESUMEN

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.


Asunto(s)
Mutación , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Alelos , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Quinasa de la Caseína II/química , Quinasa de la Caseína II/genética , Niño , Exones , Facies , Femenino , Humanos , Masculino , Unión Proteica , Dominios y Motivos de Interacción de Proteínas
5.
Am J Med Genet A ; 173(6): 1593-1600, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28440577

RESUMEN

Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients' deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Discapacidades del Desarrollo/genética , Preescolar , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Humanos , Lactante , Masculino , Monosomía
7.
Nat Genet ; 38(9): 1038-42, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16906162

RESUMEN

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.


Asunto(s)
Duplicación de Gen , Genoma Humano , Discapacidad Intelectual/genética , Rotura Cromosómica , Deleción Cromosómica , Cromosomas Artificiales Bacterianos , Cromosomas Humanos Par 17 , Dosificación de Gen , Reordenamiento Génico , Heterocigoto , Humanos , Hibridación Fluorescente in Situ , Mosaicismo , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapeo Físico de Cromosoma , Polimorfismo Genético
8.
Dev Med Child Neurol ; 53(7): 664-8, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21649651

RESUMEN

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose<2.2 mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five individuals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early-onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion-induced dyskinesia.


Asunto(s)
Transportador de Glucosa de Tipo 1/genética , Glucosa/líquido cefalorraquídeo , Adolescente , Errores Innatos del Metabolismo de los Carbohidratos/líquido cefalorraquídeo , Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/fisiopatología , Niño , Preescolar , Diagnóstico Diferencial , Distonía/genética , Epilepsia Tipo Ausencia/genética , Femenino , Marcha , Humanos , Masculino , Proteínas de Transporte de Monosacáridos/líquido cefalorraquídeo , Proteínas de Transporte de Monosacáridos/deficiencia , Proteínas de Transporte de Monosacáridos/genética , Actividad Motora , Mutación , Fenotipo , Índice de Severidad de la Enfermedad
9.
Eur J Pediatr ; 167(12): 1399-407, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18461363

RESUMEN

The absence of a definitive genetic test for the autosomal recessive condition Schinzel-Giedion syndrome is a significant handicap to the recognition of this disorder. Radiological features have been an important aspect of many of the published cases. In a series of six cases, we now establish a consistency among many of the radiological features in affected cases which will be an important diagnostic aid in identifying future cases. This is confirmed by reference to an extensive review of previously published instances of the syndrome. Moreover, the clinical data, including previously unpublished photographs, which we detail from our patients will assist in enhanced diagnosis in the future.


Asunto(s)
Anomalías Múltiples/diagnóstico por imagen , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Múltiples/diagnóstico , Anomalías Craneofaciales/complicaciones , Anomalías Craneofaciales/diagnóstico , Femenino , Dedos/anomalías , Dedos/diagnóstico por imagen , Humanos , Hipertricosis/etiología , Lactante , Recién Nacido , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/etiología , Masculino , Uñas Malformadas/etiología , Huesos Pélvicos/anomalías , Huesos Pélvicos/diagnóstico por imagen , Radiografía , Síndrome
10.
Cochrane Database Syst Rev ; (4): CD006043, 2008 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-18843700

RESUMEN

BACKGROUND: There is considerable variation in use of pain relief for managing pain or discomfort of femoral sheath removal. Efficacy of pain relief to promote comfort during this procedure or to reduce the incidence of vascular and procedural complications has not been established. OBJECTIVES: Assess efficacy of pain relief used to manage pain of femoral sheath removal in adults after interventional cardiology.Determine if pain relief influences rate of complications associated with this procedure. SEARCH STRATEGY: Databases searched in August 2007: Cochrane Pain, Palliative and Supportive Care Group Trials Register, Cochrane Heart Group Trials Register, Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL, PubMed, Australia's Australasian Medical Index, National Research Centre, Web of Knowledge and Digital Dissertations. SELECTION CRITERIA: Randomised studies comparing opioid, local anaesthetic, anxiolytic, no treatment or placebo administered for alleviation of pain or discomfort of the femoral sheath removal procedure, were sought. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data. Weighted mean differences (WMD) were calculated where meta-analysis of pain score data was feasible. Adverse effects information was collected. MAIN RESULTS: Four trials involving 971 participants were included. All results were reported using a zero to ten pain scale. Three trials (four treatment arms) involving 498 participants compared subcutaneous lignocaine with control; with no significant difference between pain scores; WMD 0.12 (95% CI -0.46 to 0.69). Two trials (three treatment arms) involving 399 participants compared intravenous pain regimens with control. A significant reduction in pain score with an intravenous pain regimen (opioid and anxiolytic) was observed when compared with placebo; WMD -0.90 (95% CI -1.54 to -0.27). One study involving 60 participants compared levobupivacaine with placebo. Longer-acting local anaesthetic significantly lowered pain score by -1.10 (95% CI -1.26 to -0.94). Data is insufficient to identify any influence of pain regimens on incidence of vascular and procedural complications. No trials reported appropriate blinding for treatment arms. The largest trial, comprising 661 participants was unblinded with a quality score of two out of five. AUTHORS' CONCLUSIONS: Intravenous pain regimens and levobupivacaine may have greater efficacy when compared to control for the management of pain related to femoral sheath removal. However, a definitive study is still required because the clinical difference is small. There is no evidence to support the use of subcutaneous lignocaine for the relief of femoral sheath removal related pain. There is insufficient evidence to determine if pain relief influences the rate of complications.


Asunto(s)
Angioplastia Coronaria con Balón/instrumentación , Remoción de Dispositivos/efectos adversos , Dolor/tratamiento farmacológico , Anestésicos Locales , Bupivacaína/análogos & derivados , Arteria Femoral , Humanos , Levobupivacaína , Dolor/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Stents
11.
Eur J Hum Genet ; 23(9): 1165-70, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25424711

RESUMEN

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.


Asunto(s)
Blefarofimosis/genética , Hipotiroidismo Congénito/genética , Anomalías Craneofaciales/genética , Exones , Cardiopatías Congénitas/genética , Histona Acetiltransferasas/genética , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/genética , Riñón/anomalías , Mutación , Rótula/anomalías , Trastornos Psicomotores/genética , Escroto/anomalías , Anomalías Urogenitales/genética , Blefarofimosis/diagnóstico , Blefarofimosis/patología , Preescolar , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/patología , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/patología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Exoma , Facies , Femenino , Expresión Génica , Estudios de Asociación Genética , Genotipo , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/patología , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/patología , Riñón/patología , Masculino , Rótula/patología , Fenotipo , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/patología , Escroto/patología , Índice de Severidad de la Enfermedad , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/patología
12.
Am J Cardiol ; 90(3): 222-6, 2002 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-12127607

RESUMEN

There are limited prospective angiographic data on stent deployment for long coronary lesions. This multicenter prospective study enrolled 120 patients with a single de novo stenosis >20 mm in length, in a native vessel > or =3 mm diameter, suitable for a MultiLink stent 25 to 35 mm in length with additional stent deployment if required. Quantitative angiography before and immediately after stenting and at 6-month follow-up assessed restenosis for the complete lesion and for 5-mm segments of the stented and adjacent nonstented vessel. By 1 year, myocardial infarction had occurred in 3% and target vessel repeat revascularization in 12% of patients. The mean stented length (35.8 +/- 14.6 mm) closely matched mean lesion length (30.1 +/- 13.5 mm). Restenosis to > or =50% diameter loss occurred in 32% of patients, but to > or =70% in only 8%. Of the 147 segments (5 mm in length) with baseline stenosis <25%, only 3 patients (2%) developed restenosis of > or =50%, and only in 1 of these was it > or =70%. Stenting of long narrowings is associated with good clinical outcome and a low rate of severe restenosis. Mildly diseased segments of long lesions covered by a stent rarely became severely narrowed and had negligible influence on the overall restenosis rate. These data support a strategy of full lesion coverage by stent deployment.


Asunto(s)
Angina de Pecho/terapia , Angiografía Coronaria , Estenosis Coronaria/patología , Estenosis Coronaria/terapia , Stents , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Estudios Prospectivos , Recurrencia
13.
Paediatr Nurs ; 15(3): 24-7, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12715586

RESUMEN

In 1994, the UKCC directed employers 'only to appoint persons into posts for which they have been appropriately by their programme of education and training leading to registration'. As part of a larger study into the expectations that NHS organisations have of newly qualified children's nurses, data were collected on the nursing registrations employers stipulated when wishing to appoint D grade staff to their children's wards. The survey was initially undertaken in 1998 and repeated in 2002. A letter requesting an application pack for 'a position as a D grade staff nurse on your children's ward/s' was sent to English NHS trusts identified as having a children's service. In 1998, 28 out of 47 (56 per cent) of the trusts appeared willing to employ nurses without a children's nursing qualification, indicating that a registered general nurse (RGN) or enrolled nurse qualification (EN) would be acceptable. In 2002, 12 of the trusts had changed their registration requirements for the D grade post since 1998 but four (out of 19 that provided data) were still apparently willing to employ non-children's nurses on children's wards. The size of the sample makes it inappropriate to generalize the results across all acute NHS trusts but there are indications that in spite of government policy and recommendations, some trusts appear willing to consider employing nurses without a children's qualification on children's wards.


Asunto(s)
Empleo/organización & administración , Enfermería Pediátrica , Selección de Personal/organización & administración , Admisión y Programación de Personal/organización & administración , Medicina Estatal/organización & administración , Movilidad Laboral , Humanos , Licencia en Enfermería , Evaluación de Necesidades , Rol de la Enfermera , Investigación en Administración de Enfermería , Enfermería Pediátrica/educación , Sistema de Registros , Reino Unido , Recursos Humanos
14.
Orphanet J Rare Dis ; 9: 23, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24524299

RESUMEN

BACKGROUND: Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1. METHODS: We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed. RESULTS: EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele. CONCLUSIONS: EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.


Asunto(s)
Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Atrofias Olivopontocerebelosas/genética , Proteínas de Unión al ARN/genética , Encéfalo/patología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Mutación
15.
Arch Dis Child ; 98(12): 1004-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24047924

RESUMEN

Mutations in the recently described RARS2 gene encoding for mitochondrial arginyl-transfer RNA synthetase give rise to a disorder characterised by early onset seizures, progressive microcephaly and developmental delay. The disorder was named pontocerebellar hypoplasia type 6 (PCH6) based on the corresponding radiological findings observed in the original cases. We report two siblings with the RARS2 mutation who displayed typical clinical features of PCH6, but who had distinct neuroimaging features. Early scans showed marked supratentorial, rather than infratentorial, atrophy, and the pons remained preserved throughout. One sibling also had bilateral subdural effusions at presentation. The deceleration in head growth pointed to an evolving genetic/metabolic process giving rise to cerebral atrophy and secondary subdural effusions. RARS2 mutations should be considered in infants presenting with seizures, subdural effusions, decelerating head growth and evidence of cerebral atrophy even in the absence of pontocerebellar hypoplasia on imaging.


Asunto(s)
Arginino-ARNt Ligasa/genética , Cerebelo/anomalías , Atrofias Olivopontocerebelosas/genética , Puente/anomalías , Efusión Subdural/genética , Cerebelo/patología , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Mutación , Atrofias Olivopontocerebelosas/diagnóstico , Puente/patología , Hermanos , Efusión Subdural/diagnóstico , Efusión Subdural/patología
18.
Hum Mol Genet ; 16(5): 567-72, 2007 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-17360722

RESUMEN

We describe multiple individuals with mental retardation and overlapping de novo submicroscopic deletions of 15q24 (1.7-3.9 Mb in size). High-resolution analysis showed that in three patients both proximal and distal breakpoints co-localized to highly identical segmental duplications (>51 kb in length, > 94% identity), suggesting non-allelic homologous recombination as the likely mechanism of origin. Sequencing studies in a fourth individual provided base pair resolution and showed that both breakpoints in this case were located in unique sequence. Despite the differences in the size and location of the deletions, all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue) and resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip), indicating that this represents a novel syndrome caused by haploinsufficiency of one or more dosage-sensitive genes in the minimal deletion region. Our results define microdeletion of 15q24 as a novel recurrent genomic disorder.


Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Adolescente , Adulto , Secuencia de Bases , Rotura Cromosómica , Análisis Mutacional de ADN , Humanos , Masculino , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Síndrome
19.
Hum Genet ; 111(4-5): 376-87, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12384779

RESUMEN

Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth restriction (PNGR) and additional dysmorphic features including body asymmetry and fifth finger clinodactyly. The syndrome is genetically heterogeneous, with a number of chromosomes implicated. However, maternal uniparental disomy for chromosome 7 has been demonstrated in up to 10% of all cases. Three SRS probands have previously been described with a maternally inherited duplication of 7p11.2-p13, defining this as a candidate region. Over-expression of a maternally transcribed, imprinted gene with growth-suppressing activity located within the duplicated region, or breakpoint disruption of genes or regulatory sequences, may account for the phenotype in these cases. Here we describe two additional SRS patients and four probands with PNGR with a range of cytogenetic disruptions of 7p, including duplications, pericentric inversions and a translocation. An incomplete contig consisting of 80 PACs and BACs from the centromere to 7p14 was constructed. Individual clones from this contig were used as FISH probes to map the breakpoints in the six new cases and the three duplication probands previously described. Our data provide further evidence for a candidate SRS region at 7p11.1-p14. A common breakpoint region was identified within 7p11.2 in all nine cases, pinpointing this specific interval. The imprinting status of genes within the 7p11.1-p14 region flanked by the most extreme breakpoints have been analysed using both somatic cell hybrids containing a single full-length maternally or paternally derived chromosome 7 and expressed single nucleotide polymorphisms in paired fetal and maternal samples.


Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 7 , Impresión Genómica , Secuencia de Bases , Cartilla de ADN , Retardo del Crecimiento Fetal/genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
20.
Catheter Cardiovasc Interv ; 59(2): 165-71, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12772233

RESUMEN

Retrospective analyses of patient cohorts undergoing stent deployment have shown that small vessel diameter and long lesion length are two angiographic predictors of increased restenosis. We determined the effects of these factors in patients with lesions treated in both small- and large-diameter coronary arteries. This multicenter prospective quantitative angiographic study evaluated patients with de novo coronary disease undergoing intervention who had at least two lesions < or = 16 mm length, one in a vessel < or = 2.75 mm diameter (9 or 16 mm length seven-cell NIR stent) and the other in a vessel > or = 3.0 mm diameter (9 or 16 mm nine-cell NIR stent). Of 94 patients enrolled, 76% were male, mean age was 62 years (range, 40-85), 41% were hypertensive, 18% had diabetes, 15% were current smokers, and 64% had hypercholesterolemia. Additional lesions were treated in 23% of patients. The procedural success rate was 99%. Six months postprocedure, there were no deaths or late stent occlusions. One patient suffered a Q-wave myocardial infarction, one a non-Q-wave infarction, eight underwent percutaneous reintervention, two coronary artery bypass graft surgery operations, and five stenting of other nonstudy lesions. The mean reference diameter for the small vessel was 2.35 mm and the large vessel 3.22 mm. Six-month angiography was performed in 87 patients (92% of those eligible). The overall restenosis rate was 24% in the small vessel (9 mm length stent, 17%; 16 mm length stent, 30%) and 15% in the large vessel (9 mm length stent, 3%; 16 mm length stent, 22%), respectively. Multivessel stenting including treatment of lesions in small-caliber vessels can be performed with a good clinical and angiographic outcome. When the patient, operator, technique, and stent type are the same, vessel caliber and stent length both appear to influence the restenosis rate.


Asunto(s)
Reestenosis Coronaria/terapia , Vasos Coronarios/patología , Vasos Coronarios/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Angioplastia Coronaria con Balón , Implantación de Prótesis Vascular , Angiografía Coronaria , Puente de Arteria Coronaria , Reestenosis Coronaria/diagnóstico , Reestenosis Coronaria/epidemiología , Diseño de Equipo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Stents , Factores de Tiempo , Resultado del Tratamiento
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