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Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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Anomalías Múltiples/genética , Cara/anomalías , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Estudios de Cohortes , Estudios de Asociación Genética/métodos , HumanosRESUMEN
The recent advent of noninvasive prenatal testing (NIPT) has had a significant impact in the field of prenatal testing. Although reports on pregnant women who used NIPT have accumulated, little is known about the experiences of their male partners. In this study, we assessed the experiences of couples who were expecting a child and undergoing NIPT, with a focus on both the pregnant women and their partners. Questionnaires were administered to 282 participants focusing on their specific experiences at three time points: after pre-test counseling (first visit), when undergoing NIPT (second visit), and when results were received (third visit). Responses were analyzed to assess the differences between pregnant women and their partners. We found that more partners selected "family" as their first information source about NIPT and "my partner" as the first person to request NIPT than did pregnant women (35.6 vs. 5.9 %; p < 0.001 and 19.3 vs.1.5 %; p < 0.001). However, pregnant women more often consulted others including family and friends until undergoing NIPT than their partners (89.1 vs. 54.6 %; p < 0.001). Our findings suggest that it is important to encourage male partners to be actively involved in the NIPT decision-making process. Differences between pregnant women and their partners should be seriously considered when providing genetic counseling.
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Asesoramiento Genético , Pruebas Genéticas , Diagnóstico Prenatal , Esposos , Adulto , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , EmbarazoRESUMEN
Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by moderate or severe intellectual disability, a characteristic facial appearance, microcephaly, epilepsy, agenesis or hypoplasia of the corpus callosum, congenital heart defects, Hirschsprung disease, and urogenital/renal anomalies. It is caused by de novo heterozygous loss of function mutations including nonsense mutations, frameshift mutations, and deletions in ZEB2 at 2q22. ZEB2 encodes the zinc finger E-box binding homeobox 2 protein consisting of 1,214 amino acids. Herein, we report 13 nonsense and 27 frameshift mutations from 40 newly identified MWS patients in Japan. Although the clinical findings of all the Japanese MWS patients with nonsense and frameshift mutations were quite similar to the previous review reports of MWS caused by nonsense mutations, frameshift mutations and deletions of ZEB2, the frequencies of microcephaly, Hirschsprung disease, and urogenital/renal anomalies were small. Patients harbored mutations spanning the region between the amino acids 55 and 1,204 in wild-type ZEB2. There was no obvious genotype-phenotype correlation among the patients. A transfection study demonstrated that the cellular level of the longest form of the mutant ZEB2 protein harboring the p.D1204Rfs*29 mutation was remarkably low. The results showed that the 3'-end frameshift mutation of ZEB2 causes MWS due to ZEB2 instability.
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Estudios de Asociación Genética , Enfermedad de Hirschsprung/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Proteínas Represoras/genética , Adolescente , Adulto , Alelos , Línea Celular , Niño , Preescolar , Codón sin Sentido , Facies , Femenino , Mutación del Sistema de Lectura , Expresión Génica , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/epidemiología , Proteínas de Homeodominio/metabolismo , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Japón , Masculino , Microcefalia/diagnóstico , Microcefalia/epidemiología , Fenotipo , Prevalencia , Estabilidad Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Adulto Joven , Caja Homeótica 2 de Unión a E-Box con Dedos de ZincRESUMEN
Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.
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Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Enfermedades Hematológicas/genética , Histona Demetilasas/genética , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/diagnóstico , Adolescente , Adulto , Sustitución de Aminoácidos , Niño , Preescolar , Exoma , Facies , Femenino , Estudios de Asociación Genética , Enfermedades Hematológicas/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Tasa de Mutación , Fenotipo , Enfermedades Vestibulares/diagnóstico , Inactivación del Cromosoma X , Adulto JovenRESUMEN
Background: The 5p- syndrome is associated with intellectual disturbance and physical complications from infancy, and patients continue treatment into adulthood. This study aimed to clarify the factors that facilitate and prevent healthcare transition from pediatric to adult care by conducting a questionnaire survey among medical professionals. Subjects: The survey included 81 medical professionals nominated by an association of families of 5p- patients in Japan. The questions involved medical care for 5p- syndrome in adulthood, experience of transition, and factors facilitating a patient's transition. Responses were obtained from 32 participants, with 27 answers eligible for analysis. Results: The questionnaire items involved physical symptoms and concerns regarding support and welfare prompting consult. The most common physical symptom was constipation. Regarding support and welfare, all participants had an experience of receiving consultation about care for the siblings of patients. Three (11.1%) participants had an experience of transition. Regarding the transition of patients with rare diseases or intellectual disturbance, only four (14.8%) believed that progress was being made in the transition. Discussion: Only 11% of the respondents experienced the transition of patients with 5p- syndrome. Because it is difficult for highly specialized adult care providers to deal with multidisciplinary complications of 5p- syndrome and information on prognosis and natural history is not known, it is presumed that the transition of 5p- syndrome did not progress. Factors to improve the transition of patients with 5p- syndrome and are likely to be effective for the transition of patients with other rare diseases or intellectual disabilities.
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BACKGROUND: International reporting of epidemiological surveys of spinal muscular atrophy (SMA) in Japan has been limited to Shikoku, despite the epidemiology of the disease in countries worldwide becoming clearer. Treatments of 5q-SMA have been developed, and epidemiological studies are needed. PURPOSE: This study aimed to conduct a nationwide epidemiological survey of SMA in Japan to clarify the actual situation of SMA in Japan. METHOD: Patients with all clinical types of SMA, including neonates and adults, were selected from 1,005 medical facilities in Japan. RESULTS: As of December 2017, the actual number of reported patients with SMA was 658 and the genetic testing rate was 79.5%. The estimated number of patients was 1,478 (95% confidence interval (CI), 1,122-1,834), with a prevalence of 1.17 (95%CI, 0.89-1.45) per 100,000 people and an incidence of 0.51 (95%CI, 0.32-0.71) per 10,000 live births. Incidence rates of 5q-SMA by clinical type were 0.27 (95%CI, 0.17-0.38) and 0.08 (95%CI, 0.04-0.11) per 10,000 live births for type 1 and 2, respectively, in cases with a definitive diagnosis by genetic testing. We found that 363 cases (82.7%) occurred less than 2 years and 88 (20.0%) occurred age of 2 months old or under. CONCLUSION: This study clarifies the prevalence and incidence of SMA in Japan. As infantile onset accounts for most cases of SMA, newborn screening and subsequent treatment are important to save lives.
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Atrofia Muscular Espinal/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Epidemiológicos , Femenino , Pruebas Genéticas , Humanos , Incidencia , Lactante , Japón/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
A relatively small region of human chromosome 21 (Hsa21) is considered to play a major role in Down syndrome (DS) phenotypes, and the concept of a Down syndrome critical region (DSCR) has been proposed. The goal of the phenotype-genotype correlation study is to discover which genes are responsible for each DS phenotype. Loss of the genomic copy numbers of Hsa21 can give us important suggestion to understand the functions of the involved genes. Genomic copy number aberrations were analyzed by micro-array-based comparative genomic hybridization (aCGH) in 300 patients with developmental delay. Partial deletions of Hsa21 were identified in three patients with developmental delay, epilepsy, microcephaly, and distinctive manifestations. Two of the patients had mosaic deletions of 21q22-qter including a part of DSCR; one of whom whose mosaic ratio was higher than the other showed more severe brain morphogenic abnormality with colpocephaly, which was similar to the previously reported patients having pure deletions of 21q22-qter, indicating the critical region for cortical dysplasia at this region. The remaining patient had the smallest microdeletion with 480 kb in DSCR including DYRK1A and KCNJ6. Although we could not identify any nucleotide alteration in DYRK1A and KCNJ6 in our cohort study for 150 patients with mental retardation with/without epilepsy, this study underscores the clinical importance of DSCR not only for DS but also for developmental disorders.
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Deleción Cromosómica , Cromosomas Humanos Par 21/genética , Discapacidades del Desarrollo/genética , Síndrome de Down/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Estudios de Cohortes , Hibridación Genómica Comparativa , Análisis Citogenético , Discapacidades del Desarrollo/patología , Síndrome de Down/patología , Humanos , Análisis por Micromatrices , Quinasas DyrKRESUMEN
With the advance of technology of genetic research, a lot of genetic testing has been available as a clinical service. The genetic testing has sometimes been applied to not only diagnosis of a patient, but also pre-symptomatic diagnosis, prenatal diagnosis, carrier diagnosis, and susceptibility diagnosis. Genetic knowledge and psychological support are necessary for the subject for adequate voluntary decision making. Thus genetic counseling by a clinical geneticist or a genetic counselor is very important and must be offered on every genetic testing according to the Guidelines for genetic testing proposed by Genetic-Medicine-Related Societies.
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Asesoramiento Genético , Mutación , Femenino , Humanos , EmbarazoRESUMEN
We herein report 3 cases of Mowat-Wilson syndrome, characterized by distinct facial features, severe psychomotor retardation, and epilepsy, recurring in 3 siblings from the same parents. The proband was a 15-month-old boy, the youngest of 3 children (2 elder sisters), who was referred to our hospital for the treatment of severe seizures. The clinical features and course of these 3 siblings were compatible with those of previously reported Mowat-Wilson syndrome patients, and all siblings had the same E87X nonsense mutation in ZFHX1B, whereas their mother did not show the mutation. Because Mowat-Wilson syndrome has been caused by de novo mutation in ZFHX1B, germ-line mosaicism should be considered if recurrence in siblings is observed.
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Anomalías Craneofaciales/genética , Epilepsia/genética , Facies , Mutación de Línea Germinal/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Hermanos , Anomalías Múltiples , Niño , Preescolar , Codón sin Sentido/genética , Anomalías Craneofaciales/complicaciones , Epilepsia/complicaciones , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Masculino , Mosaicismo , Linaje , Síndrome , Caja Homeótica 2 de Unión a E-Box con Dedos de ZincRESUMEN
We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c.2698_2701 del, of EFTUD2. The epileptic focus was consistent with the reduced frontal lobe volume on head magnetic resonance imaging. Seizures are thus a main feature of mandibulofacial dysostosis with microcephaly, which results from an embryonic development defect due to the EFTUD2 mutation.
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Disostosis Mandibulofacial/genética , Disostosis Mandibulofacial/fisiopatología , Microcefalia/genética , Microcefalia/fisiopatología , Convulsiones/genética , Convulsiones/fisiopatología , Encéfalo/diagnóstico por imagen , Niño , Análisis Mutacional de ADN , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Diagnóstico Diferencial , Cara/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Disostosis Mandibulofacial/diagnóstico por imagen , Microcefalia/diagnóstico por imagen , Factores de Elongación de Péptidos/genética , Ribonucleoproteína Nuclear Pequeña U5/genética , Convulsiones/diagnóstico por imagenRESUMEN
OBJECTIVE: Serum diamine oxidase (DAO) activity varies to a greater extent in women than in men. DAO activity during the luteal phase was higher than that during the follicular phase in healthy women. Recent reports have indicated that duodenal lipid infusion increased DAO activity in the intestinal lymph in rats. The aim of this study was to elucidate the effect of dietary nutrient intake on serum DAO activity in healthy women. METHODS: Thirty-four healthy Japanese women were recruited. Food surveys were performed using dietary records for 3 d during both the follicular and luteal phases. Nutrient intake was calculated and expressed as the energy intake ratio. The correlation between DAO activity and nutrient intake was analyzed. RESULTS: Serum DAO activity in both phases was positively correlated with intake of long-chain fatty acids, saturated fatty acids, and monounsaturated fatty acids (P < 0.05). Intake of phosphorus, calcium, zinc, magnesium, iron, and vitamin B12 during the luteal phase was positively correlated with serum DAO activity (P < 0.05). CONCLUSION: In healthy women, serum DAO activity was influenced by dietary fatty acid and micronutrient intake.
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Amina Oxidasa (conteniendo Cobre)/sangre , Grasas de la Dieta/farmacología , Ingestión de Energía , Ácidos Grasos/farmacología , Micronutrientes/farmacología , Estado Nutricional , Adulto , Grasas de la Dieta/sangre , Ácidos Grasos/sangre , Femenino , Humanos , Micronutrientes/sangre , Adulto JovenRESUMEN
We report the first two Japanese children diagnosed with glucose transporter type 1 (GLUT1) deficiency syndrome. Both boys had been treated under the initial diagnosis of epilepsy and were reinvestigated for previously unexplainable hypoglycorrhachia. Myoclonic seizures developed at 4 months of age in Patient #1 (7 years old), and at 2 months of age in Patient #2 (11 years old), followed by cerebellar ataxia, spastic diplegia, and mental retardation. Both patients had hypoglycorrhachia, and the symptoms were more severe in the latter. CSF and serum glucose levels determined simultaneously showed a CSF/serum glucose ratio of below 0.4 in both patients. In mildly affected Patient #1, the postprandial waking EEG showed improvement in the background activity, as compared to that recorded after overnight fasting, while no significant changes were observed in severely affected Patient #2. In both patients, the functional GLUT1 defect was confirmed by 3-O-methyl-D-glucose uptake into erythrocytes. Molecular analyses identified heterozygous novel mutations in both patients, within exons 6 and 2 of the GLUT1 gene, respectively. The ketogenic diet was refused in Patient #1, but started in Patient #2 with significant clinical benefit. Fasting CSF analysis and pre-/postprandial EEG changes in children with epileptic seizures and unexplainable neurological deterioration help in diagnosing this potentially treatable disorder.
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Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/fisiopatología , Proteínas de Transporte de Monosacáridos/deficiencia , Proteínas de Transporte de Monosacáridos/genética , Secuencia de Bases , Encéfalo/fisiopatología , Errores Innatos del Metabolismo de los Carbohidratos/complicaciones , Niño , Electroencefalografía , Epilepsia/etiología , Glucosa/análisis , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1 , Humanos , Lactante , Japón , Masculino , Datos de Secuencia Molecular , MutaciónRESUMEN
OBJECTIVE: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. METHOD: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. RESULTS: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. CONCLUSION: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.
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Trastornos de los Cromosomas/genética , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/epidemiología , Cromosomas Humanos Par 1/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Japón/epidemiología , Masculino , Análisis por Micromatrices/métodos , Adulto JovenRESUMEN
We describe a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8 [46,XX,t(5;8)(q35;q24.1)] in a 15-month-old girl with a typical Sotos syndrome phenotype. Involvement of the 5q35 region was previously reported (Maroun et al. [1994: Am J Med Genet 50:291-293]) as one of translocation breakpoints in the present patient. We suggest that the gene responsible for Sotos syndrome is located to a distal long-arm region of chromosome 5.
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Cromosomas Humanos Par 5 , Cromosomas Humanos Par 8 , Anomalías Craneofaciales/genética , Translocación Genética , Femenino , Humanos , Lactante , SíndromeRESUMEN
We present a boy and two girls with paternal uniparental disomy of chromosome 14q (patUPD14). One girl had a Robertsonian translocation, whereas two a normal karyotype. Based on the manifestations of these patients and four previously reported patients who all had translocated chromosome 14, The patUPD14 was thought to constitute a distinctive syndrome. The hallmarks included abdominal muscular defects, skeletal anomalies, and characteristic facies. The phenotype of patUPD14 was consistent with that of a previously reported mouse model, i.e., mouse embryos with paternal uniparental disomy of chromosome 12 that has a region orthologous to that of human chromosome 14. Dose effects of newly recognized imprinted genes on human chromosome 14q32, DLK1 and GTL2, could play an important role in the pathogenic mechanism of the distinctive malformation complex.
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Anomalías Múltiples/genética , Cromosomas Humanos Par 14/genética , Disomía Uniparental/genética , Anomalías Múltiples/patología , ADN/genética , Salud de la Familia , Femenino , Humanos , Lactante , Recién Nacido , Cariotipificación , Masculino , Repeticiones de Microsatélite , LinajeAsunto(s)
Estenosis de la Válvula Aórtica/genética , Labio Leporino/genética , Fisura del Paladar/genética , Síndrome de DiGeorge/genética , Duplicaciones Segmentarias en el Genoma , Adulto , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/cirugía , Cromosomas Humanos Par 22/química , Labio Leporino/patología , Labio Leporino/cirugía , Fisura del Paladar/patología , Fisura del Paladar/cirugía , Síndrome de DiGeorge/patología , Síndrome de DiGeorge/cirugía , Humanos , Masculino , Reemplazo de la Válvula Aórtica TranscatéterRESUMEN
Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions.
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Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Estudios de Asociación Genética/métodos , Discapacidad Intelectual/genética , Proteínas Nucleares/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Adolescente , Preescolar , Bandeo Cromosómico , Variaciones en el Número de Copia de ADN , Femenino , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Fenotipo , Factores de Elongación Transcripcional , Adulto JovenRESUMEN
BACKGROUND: Triplication is a rare chromosomal anomaly. We identified a de novo triplication of 11q12.3 in a patient with developmental delay, distinctive facial features, and others. In the present study, we discuss the mechanism of triplications that are not embedded within duplications and potential genes which may contribute to the phenotype. RESULTS: The identified triplication of 11q12.3 was 557 kb long and not embedded within the duplicated regions. The aberrant region was overlapped with the segment reported to be duplicated in 2 other patients. The common phenotypic features in the present patient and the previously reported patient were brain developmental delay, finger abnormalities (including arachnodactuly, camptodactyly, brachydactyly, clinodactyly, and broad thumbs), and preauricular pits. CONCLUSIONS: Triplications that are not embedded within duplicated regions are rare and sometimes observed as the consequence of non-allelic homologous recombination. The de novo triplication identified in the present study is novel and not embedded within the duplicated region. In the 11q12.3 region, many copy number variations were observed in the database. This may be the trigger of this rare triplication. Because the shortest region of overlap contained 2 candidate genes, STX5 and CHRM1, which show some relevance to neuronal functions, we believe that the genomic copy number gains of these genes may be responsible for the neurological features seen in these patients.
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Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.
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Fosfatasa Ácida/deficiencia , Fosfatasa Ácida/genética , Autoinmunidad , Enfermedades del Desarrollo Óseo/metabolismo , Encéfalo/metabolismo , Calcio/química , Predisposición Genética a la Enfermedad , Isoenzimas/deficiencia , Isoenzimas/genética , Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/genética , Huesos/diagnóstico por imagen , Niño , Homocigoto , Humanos , Masculino , Mutación , Osteocondrodisplasias/enzimología , Osteocondrodisplasias/genética , Osteopontina/metabolismo , Fosforilación , Radiografía , Fosfatasa Ácida TartratorresistenteRESUMEN
Deletion of the terminal end of 17p is responsible for Miller-Dieker syndrome (MDS), which is characterized by lissencephaly, distinctive facial features, growth deficiency, and intractable seizures. Using microarray-based comparative genomic hybridization, 3 patients with epilepsy were revealed to have genomic copy number aberrations at 17p13.3: a partial LIS1 deletion in a patient with isolated lissencephaly and epilepsy, a triplication of LIS1 in a patient with symptomatic West syndrome, and a terminal deletion of 17p including YWHAE and CRK but not LIS1 in a patient with intractable epilepsy associated with distinctive facial features and growth retardation. In this study, it was suggested that the identified gain or loss of genomic copy numbers within 17p13.3 result in epileptogenesis and that triplication of LIS1 can cause symptomatic West syndrome.