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1.
Nat Commun ; 12(1): 833, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547280

RESUMEN

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.


Asunto(s)
Discapacidades del Desarrollo/genética , Regulación del Desarrollo de la Expresión Génica , Microcefalia/genética , Micrognatismo/genética , Factores de Iniciación de Péptidos/genética , Proteínas de Unión al ARN/genética , Adolescente , Secuencia de Aminoácidos , Animales , Niño , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Embrión no Mamífero , Femenino , Humanos , Lisina/análogos & derivados , Lisina/genética , Lisina/metabolismo , Masculino , Microcefalia/metabolismo , Microcefalia/patología , Micrognatismo/metabolismo , Micrognatismo/patología , Factores de Iniciación de Péptidos/deficiencia , Péptidos/genética , Péptidos/metabolismo , Biosíntesis de Proteínas , Conformación Proteica , Isoformas de Proteínas/deficiencia , Isoformas de Proteínas/genética , Ribosomas/genética , Ribosomas/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Espermidina/farmacología , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
2.
Medicine (Baltimore) ; 100(1): e24224, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429816

RESUMEN

RATIONALE: Chromosomal 3q deletion is a recurrent genomic alternation, which is rarely reported in clinic. PATIENT CONCERNS: A 27-year-old woman underwent amniocentesis for cytogenetic analysis and single nucleotide polymorphism (SNP) array analysis at 27 weeks of gestation, due to ventricular septum defect in prenatal ultrasound findings. DIAGNOSES: G-banding analysis showed the karyotype of the fetus was normal and the couple also had normal karyotypes. However, SNP array detected a 1.71 Mb microdelection in 3q29, which was described as arr[hg19]3q29(194184392-195887205) × 1. There are 12 genes located in this locus. INTERVENTIONS: The couple refused SNP array to testify the 3q29 microdeletion was inherited or de novo and they chose termination of pregnancy. OUTCOMES: The deleted region in the fetus overlapped with part 3q29 microdeletion syndrome, which was characterized by learning disability, speech delay, mental deficiency, ocular abnormalities and craniofacial features. In addition, no similar/overlapping 3q29 microdeletion cases were reported according to the published literature and database. LESSONS: For the chromosomal microscopic imbalances partially overlapping with the defined pathogenic syndrome, deleted/duplicated size, genetic materials and phenotypic diversity should be taken into consideration when genetic counseling is offered by the clinicians.


Asunto(s)
Defectos del Tabique Interventricular/diagnóstico por imagen , Discapacidad Intelectual/diagnóstico , Ultrasonografía Prenatal , Adulto , Amniocentesis , Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Diagnóstico Diferencial , Femenino , Asesoramiento Genético , Cardiopatías Congénitas , Defectos del Tabique Interventricular/genética , Humanos , Discapacidad Intelectual/genética , Embarazo , Segundo Trimestre del Embarazo
3.
Am J Hum Genet ; 108(2): 357-367, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33508234

RESUMEN

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.


Asunto(s)
Proteínas Portadoras/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Espacio Intranuclear/metabolismo , Síndrome Nefrótico/genética , Síndrome Nefrótico/metabolismo , Proteínas del Tejido Nervioso/genética , Adulto , Animales , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Línea Celular , Niño , Preescolar , Codón sin Sentido , Discapacidades del Desarrollo/metabolismo , Epilepsia/metabolismo , Femenino , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Humanos , Riñón/metabolismo , Masculino , Ratones , Mutación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Fenotipo , Podocitos/metabolismo , Secuenciación del Exoma Completo
4.
Zhonghua Yi Xue Za Zhi ; 101(3): 224-228, 2021 Jan 19.
Artículo en Chino | MEDLINE | ID: mdl-33455150

RESUMEN

Objective: To study the value of chromosome microarray analysis (CMA) application in children with developmental delay (DD), intellectual disability (ID), autistic spectrum disorder (ASD) and multiple congenital anomalies (MCA). Methods: Genomic DNA was extracted from peripheral blood samples. Array-based comparative genomic hybridization (array-CGH) analysis and single nucleotide polymorphism array (SNP-array) were performed in 1 320 children with DD/ID, ASD, with or without epilepsy and MCA who were admitted to Peking University First Hospital from 2014 to 2019. The results of genetic etiology test of CMA in children with mental retardation or global DD was summarized. Results: Of 1 320 samples, there were 10 cases of aneuploid abnormality, 6 cases of uniparental disomy and one case of mosaicism, respectively. Pathogenic copy number variations (CNVs) were found in 320 cases and pathogenic CNVs were detected in 23 cases, with a combined detection rate of 26% (343/1 320). CNVs of uncertain clinical significance occurred in 107 cases, accounting for 8.1% (107/1 320). There were 25 cases of possible benign CNVs, accounting for 2% (25/1 320), while benign CNVs were reported in 20 cases, accounting for 1.5% (20/1 320). The detection rate of MCA with DD/ID was 39.8% (130/327). Conclusions: CMA has the advantages of high resolution and covering the whole genome. It can detect the chromosomal abnormalities, microdeletions and duplications seen under the microscope, thus the genetic etiology of children with mental retardation or global DD can be diagnosed.


Asunto(s)
Discapacidad Intelectual , Niño , Aberraciones Cromosómicas , Cromosomas , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/genética , Análisis por Micromatrices
5.
Nat Commun ; 12(1): 627, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33504798

RESUMEN

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.


Asunto(s)
Discapacidades del Desarrollo/genética , Genes Ligados a X , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Variación Genética , Cromosomas Humanos X/genética , Femenino , Genes Recesivos , Humanos , Patrón de Herencia/genética , Masculino , Herencia Multifactorial/genética , Mutación/genética , Fenotipo , Caracteres Sexuales
6.
Medicine (Baltimore) ; 99(51): e23864, 2020 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-33371171

RESUMEN

ABSTRACT: Schaaf-Yang syndrome (SYS) is a recently identified disorder caused by a loss-of-function mutation in a maternally imprinted gene, MAGEL2, at 15q11.2q13. Due to its extreme rarity and wide range of clinical severity, clinical suspicion is difficult for a physician. In the current study, its frequency among the Korean pediatric patients with developmental delay (DD) or intellectual disability (ID) was assessed. As the first report of Korean patients with SYS, our study aims to increase the awareness of this condition among the physicians taking care of the pediatric patients with DD/ID and hypotonia.The patients diagnosed with SYS by whole-exome sequencing (WES) among the 460 Korean pediatric patients with DD/ID were included, and their clinical and molecular features were reviewed.Four patients (0.9%) were diagnosed with SYS. Profound DD (4 patients), multiple anomalies including joint contractures and facial dysmorphism (4 patients), generalized hypotonia (3 patients), and severe respiratory difficulty requiring mechanical ventilation (3 patients) were noted in most cases, similar to those in previous reports. Sleep apnea (2 patients), autistic features (2 patients), a high grade of gastroesophageal reflux (1 patient), and seizures (1 patient) were found as well. A total of 3 different truncating MAGEL2 mutations were identified. A previously-reported mutation, to be the most common one, c.1996dupC, was found in 2 patients. The other 2 mutations, c.2217delC and c.3449_3450delTT were novel mutations. As MAGEL2 is maternally imprinted, 2 patients had inherited the MAGEL2 mutation from their respective healthy fathers.SYS is an extremely rare cause of DD/ID. However, hypotonia, joint contractures, profound DD/ID and facial dysmorphism are the suggestive clinical features for SYS. As a maternally imprinted disorder, it should be reminded that SYS may be inherited in form of a mutation from a healthy father.


Asunto(s)
Síndrome de Prader-Willi/diagnóstico , Proteínas/análisis , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Síndrome de Prader-Willi/genética , Proteínas/genética , República de Corea , Secuenciación del Exoma Completo/métodos
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(11): 1283-1286, 2020 Nov 10.
Artículo en Chino | MEDLINE | ID: mdl-33179241

RESUMEN

OBJECTIVE: To explore the genetic basis for a child featuring developmental delay, intelligent disability and language deficit. METHODS: Peripheral blood samples of the child and her parents were collected for routine G-banding karyotyping analysis and single nucleotide polymorphism array (SNP array) detection. Amniotic fluid was also sampled from the mother for karyotyping analysis and SNP array detection. RESULTS: No karyotypic abnormality was found with the child and her parents. SNP array showed that the child has carried a 761.4 kb microdeletion at 16p11.2, while her mother has carried a 444.4 kb microduplication at 15q13.3. Her father's result was negative. Further analysis showed that the 15q13.3 microduplication was inherited from her maternal grandfather who was phenotypically normal. Prenatal diagnosis showed that the fetus has inherited the15q13.3 microduplication from its mother. CONCLUSION: The child has carried a de novo 16p11.2 microdeletion, which overlaps with 16p11.2 microdeletion syndrome region, in addition with similar clinical phenotypes. The 16p11.2 microdeletion probably underlies her abnormal phenotype.


Asunto(s)
Deleción Cromosómica , Discapacidades del Desarrollo , Niño , Bandeo Cromosómico , Cromosomas Humanos Par 16 , Discapacidades del Desarrollo/genética , Femenino , Feto , Humanos , Cariotipificación , Polimorfismo de Nucleótido Simple , Embarazo , Diagnóstico Prenatal
8.
Neurology ; 95(19): e2675-e2682, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-32887777

RESUMEN

OBJECTIVE: To determine genotype-phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency. METHODS: ALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study. RESULTS: Twenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25-Q75, 49-61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype. CONCLUSIONS: Seven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Discapacidades del Desarrollo/genética , Succionato-Semialdehído Deshidrogenasa/deficiencia , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Ataxia/genética , Ataxia/fisiopatología , Niño , Simulación por Computador , Discapacidades del Desarrollo/fisiopatología , Electroencefalografía , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Mutación del Sistema de Lectura , Estudios de Asociación Genética , Células HEK293 , Heterocigoto , Homocigoto , Humanos , Técnicas In Vitro , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/fisiopatología , Masculino , Hipotonía Muscular/genética , Hipotonía Muscular/fisiopatología , Mutagénesis Sitio-Dirigida , Mutación Missense , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/fisiopatología , Sitios de Empalme de ARN , Índice de Severidad de la Enfermedad , Succionato-Semialdehído Deshidrogenasa/genética
9.
PLoS One ; 15(9): e0239738, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32976529

RESUMEN

The levels and activity of the enzyme paraoxonase 1 affect the vulnerability to the teratogenic effects of organophosphate pesticides. Mutant mice lacking the gene for paraoxonase1 (PON1-/-) are more susceptible to the toxic effects of chlorpyrifos, and were hypothesized to be more vulnerable to social behavior deficits induced by exposure to chlorpyrifos during gestation. Three experiments were performed comparing PON1-/- mice to PON1+/+ mice born to dams treated with 0.5 mg/kg chlorpyrifos or cornoil vehicle on gestational days 12-15. Chlofpyrifos-exposed male PON1-/- mouse pups had delayed development of reflexes in in the first experiment. In the second experiment, adult male and female PON1-/- mice and the female PON1+/+ mice all displayed lower social preference than the male vehicle-treated PON1+/+ mice. The PON1-/- mice and the female PON1+/+ mice displayed lower social preference compared to the PON1+/+ male mice. Male adult mice that had been exposed in utero to chlorpyrifos showed less conditioned social preference regardless of genotype. In the third study, the delayed reflex development was replicated in male and female PON1-/- mice, but chlorpyrifos did not augment this effect. Nest Odor Preference, a test of early social attachment to dam and siblings, was lower in PON1-/- mouse pups compared to PON1+/+ pups. This study shows for the first time that PON1-/- mice have a behavioral phenotype that indicates impaired reflex development and social behavior. Chlorpyrifos exposure during gestation tended to augment some of these effects.


Asunto(s)
Arildialquilfosfatasa/genética , Cloropirifos/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Discapacidades del Desarrollo/genética , Efectos Tardíos de la Exposición Prenatal/genética , Conducta Social , Teratógenos/toxicidad , Animales , Arildialquilfosfatasa/deficiencia , Femenino , Masculino , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Reflejo
10.
Rev. neurol. (Ed. impr.) ; 71(5): 171-176, 1 sept., 2020. tab
Artículo en Español | IBECS | ID: ibc-195467

RESUMEN

INTRODUCCIÓN: El retraso general del desarrollo (RGD) constituye un trastorno intelectual y del comportamiento adaptativo que aparece en los niños menores de 5 años que no consiguen alcanzar los hitos del desarrollo normal. La discapacidad intelectual se caracteriza por la limitación en el funcionamiento intelectual y en el comportamiento adaptativo, surgida en la infancia. Entre las causas frecuentes y reconocibles del RGD y de la discapacidad intelectual se encuentran los desequilibrios cromosómicos. Los arrays de hibridación genómica comparada (aCGH) han contribuido a mejorar la tasa de detección de las anomalías genéticas y ya se consideran la prueba genética de elección para la discapacidad intelectual de origen desconocido. OBJETIVO: Analizar los resultados del estudio genético con aCGH motivado por un RGD o una discapacidad intelectual en pacientes pediátricos. PACIENTES Y MÉTODOS: Análisis retrospectivo de pacientes pediátricos sometidos a seguimiento ambulatorio que fueron objeto de un estudio genético con aCGH entre 2012 y 2017. RESULTADOS: El número de pacientes sometidos al estudio con aCGH ascendió a 215. Del total, el 64,2% fueron investigados por discapacidad intelectual, y el 35,8%, por RGD. El 23,3% presentó deleciones o duplicaciones en la aCGH; el 56%, por la discapacidad intelectual; y el 44%, por el RGD, y los cromosomas 16, 22, 2 y 1 fueron los implicados con más frecuencia. CONCLUSIÓN: El presente estudio demuestra la mayor prevalencia de ambos en el sexo masculino, en consonancia con otras publicaciones precedentes. La tasa de detección de las anomalías clasificadas como patógenas resultó superior a la notificada en otros estudios


INTRODUCTION: Global developmental delay (GDD) is an intellectual and adaptive impairment in infants under 5 years of age who fail to meet expected developmental milestones. Intellectual disability is characterized by limitation in intellectual function and adaptive behavior, with onset in childhood. Frequent identifiable causes of GDD and intellectual disability are chromosomal imbalances. The array comparative genomic hybridization (aCGH) has contributed to improve the detection rate of genetic abnormalities and is considered the first-tier genetic test for unexplained intellectual disability. AIM: To analyze the results of a genetic study by aCGH due to GDD or intellectual disability in pediatric patients. PATIENTS AND METHODS: Retrospective analysis of pediatric patients followed in outpatient, which underwent a genetic study by aCGH, from 2012 to 2017. RESULTS: 215 patients were studied by aCGH. Of the total, 64.2% were investigated for intellectual disability and 35.8% for GDD. A 23.3% presented aCGH deletions or duplications, 56% for intellectual disability and 44% for GDD, with chromosomes 16, 22, 2 and 1 being the most implicated. CONCLUSION: Our study demonstrated a higher prevalence in males, according to previously published reports. The rate of detection abnormalities classified as pathogenic was higher than in other studies


Asunto(s)
Humanos , Masculino , Femenino , Preescolar , Niño , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Trastornos de los Cromosomas/diagnóstico , Discapacidad Intelectual/genética , Trastornos de los Cromosomas/genética , Estudios Retrospectivos , Eliminación de Gen
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 953-957, 2020 Sep 10.
Artículo en Chino | MEDLINE | ID: mdl-32820506

RESUMEN

OBJECTIVE: To detect genomic copy number variations (CNVs) among 145 children with unexplained mental retardation/developmental delay (MR/DD) by using low-depth whole-genome copy number variation sequencing (CNV-seq). METHODS: Peripheral blood samples were collected from the patients and subjected to DNA extraction and CNV-seq. The results were analyzed by a combination of bioinformatic tools. RESULTS: Forty-nine patients were found to carry a total of 67 CNVs with an average size of 5.27 Mb. Among these, 22 patients were assessed to carry MR/DD-related CNVs involving 21 syndromes. This gave a diagnostic rate of 15.17%(22/145) for CNVs associated with unexplained MR/DD. The corresponding regions of the 22 MR/DD-related CNVs in the human genome covered 174 MR/DD-related pathogenic genes, which have mapped to 18 sections on 10 chromosomes. CONCLUSION: Genomic CNVs-related microdeletions/duplications account for a significant proportion of unexplained MR/DD, for which CNV-seq can provide an accurate diagnosis.


Asunto(s)
Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo , Discapacidad Intelectual , Secuenciación Completa del Genoma , Niño , Deleción Cromosómica , Duplicación Cromosómica , Discapacidades del Desarrollo/genética , Genómica , Humanos , Discapacidad Intelectual/genética
13.
Am J Hum Genet ; 107(3): 555-563, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32758449

RESUMEN

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.


Asunto(s)
Trastorno del Espectro Autista/genética , Proteínas de Homeodominio/genética , Discapacidad Intelectual/genética , Proteínas del Tejido Nervioso/genética , Trastornos del Neurodesarrollo/genética , Trastorno del Espectro Autista/patología , Niño , Metilación de ADN/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Epigénesis Genética/genética , Femenino , Humanos , Discapacidad Intelectual/patología , Masculino , Mutación/genética , Trastornos del Neurodesarrollo/patología , Fenotipo , Transcriptoma/genética
14.
Gene ; 761: 145027, 2020 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-32758583

RESUMEN

OBJECTIVES: Oliver-McFarlane syndrome (OMCS) is an autosomal recessive inherited disease resulting from PNPLA6 mutations that results in intellectual impairment and profound short stature. To obtain a better understanding of the genotype-phenotype correlations for PNPLA6-related disorders, we reported the 14th OMCS case and summarized all the reported cases of OMCS. METHODS: We collected clinical biochemical and data and brain MRI data and used whole-exon gene detection and analysis tools to evaluate the pathogenicity of the variants, including PolyPhen-2 and Mutation Taster, and we also generated three-dimensional protein structures and visualized the effects of altered residues with I-TASSER and PyMOL Viewer software. RESULTS: The patient presented with trichomegaly and multiple pituitary hormone deficiencies. Brain MRI showed small pituitary and bilateral paraventricular leukomalacia. Novel variants (c.1491G > T and c.3367G > A) in the PNPLA6 gene were detected in the proband and verified by direct sequencing. Amino acid residues of Gln497 and Gly1123 are predicted to be damaging and destroy the three-dimensional protein structures of the protein. In follow-up, this patient could neither walk nor hold his head erect and had not spoken one word at the age of one year and ten months. Moreover, there is no obvious hot spot mutation in any of the reported allelic variants. Interestingly, the majority of mutations are located in the phospholipid esterase domain, which is responsible for esterase activity. CONCLUSIONS: We identified two novel variants of the PNPLA6 gene in an OMCS patient, which will help to better understand the function of PNPLA6 and genotype-phenotype correlations for PNPLA6-related disorders.


Asunto(s)
Blefaroptosis/diagnóstico , Blefaroptosis/genética , Enanismo/diagnóstico , Enanismo/genética , Hipertricosis/diagnóstico , Hipertricosis/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Fosfolipasas/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Alelos , China , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Genotipo , Humanos , Lactante , Masculino , Mutación , Fenotipo , Fosfolipasas/metabolismo
15.
Nat Commun ; 11(1): 3920, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32764605

RESUMEN

How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.


Asunto(s)
Discapacidades del Desarrollo/genética , Epigénesis Genética , Organogénesis/genética , Animales , Animales Modificados Genéticamente , Bases de Datos Genéticas , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Código de Histonas/genética , Humanos , Modelos Genéticos , Mutación , Organogénesis/fisiología , Regiones Promotoras Genéticas , Distribución Tisular , Factores de Transcripción/metabolismo , Pez Cebra/embriología , Pez Cebra/genética
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 851-854, 2020 Aug 10.
Artículo en Chino | MEDLINE | ID: mdl-32761593

RESUMEN

OBJECTIVE: To explore the genetic basis for a child with global developmental delay and neurofibromatosis type 1 (NF1). METHODS: The patient underwent clinical examination. Whole exome sequencing (WES) was carried out to detect pathogenic genetic variants. RESULTS: The child had cafe au lait spots all over her body, pigmentation in the back, and global developmental delay as assessed by Gese II. Cranial MRI revealed globular abnormal density in the lower hemisphere of left posterior cranial fossa. WES detected a novel variant of the NF1 gene, c.6513-6515del (p.Tyr2171), which was strongly correlated with her clinical phenotype. The same variant was not found in either parent and was unreported previously. CONCLUSION: The c.3842T>G variant of the NF1 gene probably underlay the NF1 and global developmental delay in this child, for whom prompt symptomatic treatment and regular follow-up were recommended.


Asunto(s)
Discapacidades del Desarrollo , Genes de Neurofibromatosis 1 , Pruebas Genéticas , Neurofibromatosis 1 , Manchas Café con Leche/diagnóstico , Manchas Café con Leche/genética , Niño , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Femenino , Humanos , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genética , Fenotipo
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 867-870, 2020 Aug 10.
Artículo en Chino | MEDLINE | ID: mdl-32761597

RESUMEN

OBJECTIVE: To explore the genetic basis for a child with developmental delay and mental retardation. METHODS: Chromosomal karyotype of the child was analyzed by G-, C- and N-banding techniques. Her genome DNA was analyzed with single nucleotide polymorphisms array (SNP array). The result was validated by fluorescence quantitative polymerase chain reaction (PCR). RESULTS: The karyotype of the child was ascertained as 46,XX,r(22)(p12q13). SNP array has revealed a deletion of approximately 1.4 Mb at 22q13.33 (49 802 963-51 197 766). The deletion has encompassed the SHANK3, a crucial gene for the development of nervous system. Fluorescence quantitative PCR has confirmed the deletion of exons 7, 19 and 22 of the SHANK3 gene. CONCLUSION: The phenotype of the patient may be attributed to the microdeletion at 22q13.33. Cytogenetic methods combined with SNP array and fluorescence quantitative PCR can identify aberrant chromosomes and provide accurate information for the clinical diagnosis and genetic counseling.


Asunto(s)
Análisis Citogenético , Discapacidades del Desarrollo/genética , Discapacidad Intelectual , Niño , Bandeo Cromosómico , Deleción Cromosómica , Cromosomas Humanos Par 22 , Femenino , Humanos , Discapacidad Intelectual/genética , Cariotipificación , Polimorfismo de Nucleótido Simple
18.
PLoS Genet ; 16(8): e1008967, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32813698

RESUMEN

Dysregulation of ribosome production can lead to a number of developmental disorders called ribosomopathies. Despite the ubiquitous requirement for these cellular machines used in protein synthesis, ribosomopathies manifest in a tissue-specific manner, with many affecting the development of the face. Here we reveal yet another connection between craniofacial development and making ribosomes through the protein Paired Box 9 (PAX9). PAX9 functions as an RNA Polymerase II transcription factor to regulate the expression of proteins required for craniofacial and tooth development in humans. We now expand this function of PAX9 by demonstrating that PAX9 acts outside of the cell nucleolus to regulate the levels of proteins critical for building the small subunit of the ribosome. This function of PAX9 is conserved to the organism Xenopus tropicalis, an established model for human ribosomopathies. Depletion of pax9 leads to craniofacial defects due to abnormalities in neural crest development, a result consistent with that found for depletion of other ribosome biogenesis factors. This work highlights an unexpected layer of how the making of ribosomes is regulated in human cells and during embryonic development.


Asunto(s)
Discapacidades del Desarrollo/genética , Desarrollo Embrionario/genética , Factor de Transcripción PAX9/genética , Ribosomas/genética , Animales , Nucléolo Celular/genética , Discapacidades del Desarrollo/patología , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Cresta Neural/crecimiento & desarrollo , Cresta Neural/metabolismo , Cresta Neural/patología , Biosíntesis de Proteínas/genética , ARN Polimerasa II/genética , Ribosomas/patología , Xenopus/genética , Xenopus/crecimiento & desarrollo
19.
BMC Med Genet ; 21(1): 140, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32605629

RESUMEN

BACKGROUND: Cohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations. CASE PRESENTATION: A 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies. CONCLUSION: We reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia.


Asunto(s)
Dedos/anomalías , Discapacidad Intelectual/genética , Microcefalia/genética , Hipotonía Muscular/genética , Mutación/genética , Miopía/genética , Obesidad/genética , Degeneración Retiniana/genética , Proteínas de Transporte Vesicular/genética , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Humanos , Fenotipo
20.
Pediatrics ; 146(2)2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32709737

RESUMEN

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets.


Asunto(s)
Intolerancia a la Fructosa/diagnóstico , Adulto , Anciano , Enfermedades Asintomáticas , Niño , Preescolar , Discapacidades del Desarrollo/genética , Pruebas Dirigidas al Consumidor , Enanismo/genética , Insuficiencia de Crecimiento/genética , Femenino , Preferencias Alimentarias , Intolerancia a la Fructosa/genética , Fructosa-Bifosfato Aldolasa/genética , Frutas/efectos adversos , Pruebas Genéticas , Humanos , Hallazgos Incidentales , Infertilidad Femenina , Masculino , Atención Preconceptiva , Verduras/efectos adversos , Secuenciación del Exoma Completo
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