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1.
Adv Neurobiol ; 24: 83-96, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32006357

RESUMEN

Autism spectrum disorder (ASD) is a heterogeneous condition affecting >1% of all children, characterized by impaired social interactions, repetitive behavior and a widely variable spectrum of comorbidities. These comorbidities may include developmental delay, gastrointestinal problems, cardiac disorders, immune and autoimmune dysregulation, neurological manifestations (e.g., epilepsy, intellectual disability), and other clinical features. This wide phenotypic heterogeneity is difficult to predict and manifests across a wide range of ages and with a high degree of difference in severity, making disease management and prediction of a successful intervention very difficult. Recently, advances in genomics and other molecular technologies have enabled the study of ASD on a molecular level, illuminating genes and pathways whose perturbations help explain the clinical variability among patients, and whose impairments provide possible opportunities for better treatment options. In fact, there are now >1000 genes that have been linked to ASD through genetic studies of more than 10,000 patients and their families. This chapter discusses these discoveries and in the context of recent developments in genomics and bioinformatics, while also examining the trajectory of gene discovery efforts over the past few decades, as both better ascertainment and global attention have been given to this highly vulnerable patient population.


Asunto(s)
Trastorno del Espectro Autista/genética , Genoma Humano/genética , Genómica , Trastorno del Espectro Autista/complicaciones , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 52-56, 2020 Jan 10.
Artículo en Chino | MEDLINE | ID: mdl-31922597

RESUMEN

OBJECTIVE: To delineate the clinical features,inheritance pattern, and genotype-phenotype correlation of a Chinese patient with a 17q25.3 duplication. METHODS: Whole exome sequencing(WES), chromosomal microarray analysis (CMA), chromosomal karyotyping and fluorescence in situ hybridization (FISH) were employed for the analysis of the proband and his family members. RESULTS: A 5.7 Mb duplication at 17q25.3→qter was identified by WES and CMA in the 4-year-old boy with multiple congenital anomalies, which was classified as a clinically pathogenic variant. This duplication was confirmed by FISH, and was inherited from his unaffected mother who carried a balanced translocation. Further study revealed that his grandmother also carried the balanced translocation but had gestated three healthy children and had no abortion history. His uncle also carried the balanced translocation, while his aunt was normal. CONCLUSION: Above results have enriched the clinical phenotypes of 17q25.3 duplication. Genetic counseling was provided for the family. P4HB, ACTG1, BAIAP2 and TBCD genes may underlie the clinical features for the 17q25.3 duplication.


Asunto(s)
Anomalías Múltiples , Duplicación Cromosómica , Cromosomas Humanos Par 17 , Discapacidades del Desarrollo , Anomalías Múltiples/genética , Adulto , Preescolar , China , Cromosomas Humanos Par 17/genética , Discapacidades del Desarrollo/genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Proteínas Asociadas a Microtúbulos , Translocación Genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 64-66, 2020 Jan 10.
Artículo en Chino | MEDLINE | ID: mdl-31922600

RESUMEN

OBJECTIVE: To explore the genetic basis of a child with developmental delay and intellectual disability. METHODS: Peripheral blood samples of the child and his parents were collected for routine G-band karyotyping analysis and single nucleotide polymorphism array (SNP array) assay. Amniotic fluid sample was collected during the next pregnancy for prenatal diagnosis. RESULTS: No karyotypic abnormality was found in the child and his parents. SNP array showed that the child has carried a 855.3 kb microduplication in 15q11.2. His mother carried the same duplication but had no phenotypic anomaly. No microdeletion/microduplication was found in his father. Upon prenatal diagnosis, no abnormalities was found with the chromosomal karyotype and SNP array result of the fetus. CONCLUSION: 15q11.2 microduplication may result in developmental delay and intellectual disability, for which CYFIP1 may be a candidate gene. However, the duplication may increase the risk but with a low penetrance. This should attract attention during clinical consultation.


Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos Par 15 , Discapacidad Intelectual , Proteínas Adaptadoras Transductoras de Señales , Niño , Bandeo Cromosómico , Cromosomas Humanos Par 15/genética , Discapacidades del Desarrollo/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Cariotipificación , Masculino , Embarazo , Diagnóstico Prenatal
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1219-1221, 2019 Dec 10.
Artículo en Chino | MEDLINE | ID: mdl-31813152

RESUMEN

OBJECTIVE: To analyze the clinical phenotype and genomic abnormality of an adult featuring congenital heart defect and multiple developmental disorders. METHODS: The patient was subjected to conventional G-banding chromosomal karyotyping and single nucleotide polymorphism microarray (SNP-array) analysis. RESULTS: The patient showed a normal karyotype, while SNP-array revealed a 42.7 Mb mosaic uniparental disomy (UPD) in the 11p15.5p12 region ([hg19] chr11: 491 333-43 189 376). CONCLUSION: The mosaicism of UPD of 11p15.5p12 region probably underlies the congenital heart defect and developmental disorders in the patient.


Asunto(s)
Discapacidades del Desarrollo/genética , Cardiopatías Congénitas/genética , Mosaicismo , Disomía Uniparental , Adulto , Bandeo Cromosómico , Pruebas Genéticas , Humanos , Cariotipificación , Fenotipo , Polimorfismo de Nucleótido Simple
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1111-1114, 2019 Nov 10.
Artículo en Chino | MEDLINE | ID: mdl-31703138

RESUMEN

OBJECTIVE: To explore the clinical features and molecular basis for a child featuring infantile epilepsy and developmental disorders. METHODS: Clinical data and peripheral blood samples of the child and his parents were collected. The coding regions of genes associated with nervous system development were subjected to target region capture sequencing. RESULTS: The child developed generalized spasm at 3 months and was diagnosed with epilepsy at 6 months of age. He was treated with Depakin but was diagnosed with mental retardation and developmental retardation at 3 years of age. A novel heterozygous c.3842T to G variant of the SYNE1 gene was detected. His father was found to carry the same variant and had a history of convulsions in infancy but with no mental or developmental anomalies. CONCLUSION: A novel variant of SYNE1 gene was identified in this child, and the prognosis may be poor.


Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Preescolar , Proteínas del Citoesqueleto , Discapacidades del Desarrollo/complicaciones , Epilepsia/complicaciones , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Masculino , Mutación , Convulsiones
6.
Nat Commun ; 10(1): 4679, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31616000

RESUMEN

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.


Asunto(s)
Trastornos Mentales/genética , Proteínas del Tejido Nervioso/metabolismo , Trastornos del Neurodesarrollo/genética , Proteínas/genética , Adolescente , Adulto , Animales , Trastorno Autístico/genética , Trastorno Autístico/psicología , Conducta Animal , Encéfalo/metabolismo , Niño , Preescolar , Anomalías Craneofaciales/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/psicología , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Epilepsia/genética , Femenino , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/psicología , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/psicología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Trastornos Mentales/psicología , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutación , Trastornos del Neurodesarrollo/psicología , Neuroglía/metabolismo , Neuronas/metabolismo , Proteínas/metabolismo , Secuenciación del Exoma Completo , Adulto Joven
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1010-1014, 2019 Oct 10.
Artículo en Chino | MEDLINE | ID: mdl-31598948

RESUMEN

OBJECTIVE: To explore the genetic basis for a child with developmental delay and congenital syndactyly. METHODS: G-banding chromosomal karyotyping and chromosomal microarray analysis (CMA) were performed on peripheral blood sample from the child. RESULTS: The child was ascertained as 46, XY, r(18)[52]/45,XY,?18[3]. A 18q21.32-q23 deletion was identified by CMA with a size of 19.85 Mb, which has encompassed 99 genes including CTDP1, TXNL4A, TSHZ1, PIGN, RTTN, TNFRSF11A, KDSR and CYB5A. CONCLUSION: Clinical phenotype of the patient with ring chromosome 18 is associated with the size of the euchromatin loss and involved genes. As a useful complement to conventional karyotyping, CMA has provided an powerful tool for delineating complex chromosomal aberrations.


Asunto(s)
Aberraciones Cromosómicas , Discapacidades del Desarrollo/genética , Sindactilia/genética , Niño , Cromosomas Humanos Par 18/genética , Citogenética , Humanos , Cariotipificación , Cromosomas en Anillo
8.
Turk J Pediatr ; 61(1): 92-96, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31559727

RESUMEN

Aydin HI, Sönmez FM. A novel mutation in two cousins with guanidinoacetate methyltransferase (GAMT) deficiency presented with autism. Turk J Pediatr 2019; 61: 92-96. Guanidinoacetate methyltransferase (GAMT) deficiency is a rare autosomal recessive disorder of creatine biosynthesis. Here, we report 9 and 10-year-old cousins with GAMT deficiency caused by a novel mutation who both exhibited neurodevelopmental retardation, seizures, behavioral problems, and autism that began during early infancy. The patients were diagnosed as having only autism and followed for years without a specific diagnosis although they had very low levels of serum creatinine for several times. A novel nonsense mutation in the GAMT gene that caused cessation of synthesis of the protein encoded by this gene was identified in these patients. GAMT deficiency is a treatable inborn error of metabolism and should be considered for all patients with hypotonia, developmental delay, seizures and autism, particularly if low serum creatinine levels are observed.


Asunto(s)
Trastorno Autístico/genética , Codón sin Sentido , Guanidinoacetato N-Metiltransferasa/deficiencia , Trastornos del Desarrollo del Lenguaje/diagnóstico , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Movimiento/congénito , Niño , Creatinina/sangre , Discapacidades del Desarrollo/genética , Femenino , Guanidinoacetato N-Metiltransferasa/genética , Humanos , Masculino , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/genética , Hipotonía Muscular/genética , Convulsiones/genética
9.
Hum Genet ; 138(10): 1183-1200, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31471722

RESUMEN

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.


Asunto(s)
Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Genes Recesivos , Predisposición Genética a la Enfermedad , Mutación , Fenotipo , Transaminasas/genética , Adolescente , Alelos , Sustitución de Aminoácidos , Discapacidades del Desarrollo/metabolismo , Activación Enzimática , Exones , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genética de Población , Genotipo , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Modelos Moleculares , Linaje , Conformación Proteica , Sitios de Empalme de ARN , Análisis de Secuencia de ADN , Relación Estructura-Actividad , Transaminasas/química , Transaminasas/metabolismo
10.
Cytogenet Genome Res ; 159(1): 19-25, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31487712

RESUMEN

The role of autosomal recessive (AR) variants in clinically heterogeneous conditions such as intellectual disability and developmental delay (ID/DD) has been difficult to uncover. Implication of causative pathogenic AR variants often requires investigation within large and consanguineous families, and/or identifying rare biallelic variants in affected individuals. Furthermore, detection of homozygous gene-level copy number variants during first-line genomic microarray testing in the pediatric population is a rare finding. We describe a 6.7-year-old male patient with ID/DD and a novel homozygous deletion involving the FRY gene identified by genomic SNP microarray. This deletion was observed within a large region of homozygosity on the long arm of chromosome 13 and in a background of increased low-level (2.6%) autosomal homozygosity, consistent with a reported common ancestry in the family. FRY encodes a protein that regulates cell cytoskeletal dynamics, functions in chromosomal alignment in mitosis in vitro, and has been shown to function in the nervous system in vivo. Homozygous mutation of FRY has been previously reported in 2 consanguineous families from studies of autosomal recessive ID in Middle Eastern and Northern African populations. This report provides additional supportive evidence that deleterious biallelic mutation of FRY is associated with ID/DD and illustrates the utility of genomic SNP microarray detection of low-level homozygosity.


Asunto(s)
Proteínas de Ciclo Celular/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Eliminación de Secuencia/genética , Secuencia de Bases/genética , Niño , Consanguinidad , Citoesqueleto/genética , Citoesqueleto/metabolismo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética
12.
BMC Med Genet ; 20(1): 134, 2019 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-31382906

RESUMEN

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail. CASE PRESENTATION: Herein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family. CONCLUSION: Here, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , N-Metiltransferasa de Histona-Lisina/genética , Fenotipo , Proteínas Represoras/genética , Síndrome de Wolf-Hirschhorn/genética , Secuencia de Bases , Niño , Cromosomas Humanos Par 4 , ADN/sangre , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Convulsiones/genética , Secuenciación del Exoma Completo , Síndrome de Wolf-Hirschhorn/fisiopatología
13.
BMC Med Genomics ; 12(1): 111, 2019 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-31337399

RESUMEN

BACKGROUND: Chromosomal microarray analysis has been shown to be a valuable and cost effective assay for elucidating copy number variants (CNVs) in children with intellectual disability and developmental delay (ID/DD). METHODS: In our study, we performed array-based comparative genomic hybridization (array-CGH) analysis using oligonucleotide-based platforms in 542 Czech patients with ID/DD, autism spectrum disorders and multiple congenital abnormalities. Prior to the array-CGH analysis, all the patients were first examined karyotypically using G-banding. The presence of CNVs and their putative derivation was confirmed using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and predominantly relative quantitative polymerase chain reaction (qPCR). RESULTS: In total, 5.9% (32/542) patients were positive for karyotypic abnormalities. Pathogenic/likely pathogenic CNVs were identified in 17.7% of them (96/542), variants of uncertain significance (VOUS) were detected in 4.8% (26/542) and likely benign CNVs in 9.2% of cases (50/542). We identified 6.6% (36/542) patients with known recurrent microdeletion (24 cases) and microduplication (12 cases) syndromes, as well as 4.8% (26/542) patients with non-recurrent rare microdeletions (21 cases) and microduplications (5 cases). In the group of patients with submicroscopic pathogenic/likely pathogenic CNVs (13.3%; 68/510) we identified 91.2% (62/68) patients with one CNV, 5.9% (4/68) patients with two likely independent CNVs and 2.9% (2/68) patients with two CNVs resulting from cryptic unbalanced translocations. Of all detected CNVs, 21% (31/147) had a de novo origin, 51% (75/147) were inherited and 28% (41/147) of unknown origin. In our cohort pathogenic/likely pathogenic microdeletions were more frequent than microduplications (69%; 51/74 vs. 31%; 23/74) ranging in size from 0.395 Mb to 10.676 Mb (microdeletions) and 0.544 Mb to 8.156 Mb (microduplications), but their sizes were not significantly different (P = 0.83). The pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger than benign CNVs (median 0.394 Mb) (P < 0.00001) and likewise the pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger in size than VOUS (median 0.469 Mb) (P < 0.00001). CONCLUSIONS: Our results confirm the benefit of array-CGH in the current clinical genetic diagnostics leading to identification of the genetic cause of ID/DD in affected children.


Asunto(s)
Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adolescente , Niño , Preescolar , Estudios de Cohortes , República Checa , Femenino , Humanos , Lactante , Recién Nacido , Masculino
14.
Klin Padiatr ; 231(5): 233-239, 2019 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-31340405

RESUMEN

BACKGROUND: Shared decision-making is indispensable when it comes to molecular genetic investigations, but data on the expectations of the parents is scarce. METHODS: Using a step-by-step approach we initially performed free in-depth-interviews with five parents on which base we developed a half standardized questionnaire. This questionnaire was then applied in interviews with 30 parents of children with intellectual disability, autism or epilepsy subject to genetic examination. RESULTS: Pre-diagnostic discussions are challenging for the parents in an intellectual as well as emotional way. The most important general aspects are diagnosis and therapy. Self-assessment of prior knowledge is very variable and many parents expressed problems in understanding. During the conversation parents rate the following specific aspects as "very important" or "important": findings of unclear relevance, incidental findings, psychic consequences, prognostic aspects, possible therapeutic interventions. 10 Parents did not have any school-degree and 20 parents were not native speakers. DISCUSSION: All parents express a high need for information covering almost all aspects of the investigation. Communicational hurdles pose additional challenges leaving a large room for improvement. Trustworthy internet-based information systems in different languages including plain language could be a first step.


Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Padres/psicología , Niño , Humanos , Encuestas y Cuestionarios
15.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-31295832

RESUMEN

Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.


Asunto(s)
Encefalopatías/genética , Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Variación Genética , Canal de Potasio KCNQ2/genética , Dominios y Motivos de Interacción de Proteínas/genética , Espasmos Infantiles/genética , Sustitución de Aminoácidos , Biomarcadores , Encefalopatías/diagnóstico , Encefalopatías/terapia , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/terapia , Electroencefalografía , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Canal de Potasio KCNQ2/química , Mutación con Pérdida de Función , Imagen por Resonancia Magnética , Masculino , Modelos Moleculares , Neuroimagen , Conformación Proteica , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/terapia , Relación Estructura-Actividad , Evaluación de Síntomas
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 704-707, 2019 Jul 10.
Artículo en Chino | MEDLINE | ID: mdl-31302916

RESUMEN

OBJECTIVE: To explore the genetic basis of a child featuring intellectual disability, developmental delay and epilepsy. METHODS: Cytogenetic and molecular analysis including chromosomal karyotyping analysis, single nucleotide polymorphism array (SNP array) and qPCR were performed. RESULTS: The karyotype of the child was determined as 46, XX; SNP array: arr [19]21q22.12q22.13(36 860 195-38 801 482)×1 dn. A heterozygous 1.9 Mb microdeletion was detected at 21q22.12q22.13. qPCR has confirmed deletion of exon 1 of the DYRK1A gene, which has occurred de novo. CONCLUSION: A 21q22 deletion was diagnosed with multiple genetic methods. Genotype-phenotype correlation suggested DYRK1A to be a candidate for intellectual disability.


Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Eliminación de Secuencia , Niño , Estudios de Asociación Genética , Humanos , Cariotipificación
17.
Hum Genet ; 138(10): 1145-1153, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31321490

RESUMEN

The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33-q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1-q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1-q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10-30% of the cases. None of the 13q33-q34 deletions were inherited from a reported healthy parent. 13q33-q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.


Asunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 13 , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Bandeo Cromosómico , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Adulto Joven
18.
Nat Commun ; 10(1): 2985, 2019 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-31278258

RESUMEN

Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants.


Asunto(s)
Discapacidades del Desarrollo/genética , Exoma/genética , Mosaicismo , Secuenciación del Exoma Completo/métodos , Niño , Estudios de Cohortes , Discapacidades del Desarrollo/diagnóstico , Femenino , Pruebas Genéticas/métodos , Variación Genética , Haplotipos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Herencia Materna/genética , Padres , Herencia Paterna/genética
19.
Nat Commun ; 10(1): 2373, 2019 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-31147538

RESUMEN

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance.


Asunto(s)
Discapacidades del Desarrollo/genética , Pruebas Genéticas , Genoma Humano , Secuenciación del Exoma Completo , Alelos , Genotipo , Humanos , Técnicas de Diagnóstico Molecular , Mutación , Fenotipo , Análisis de Secuencia de ADN , Secuenciación Completa del Genoma
20.
J Pediatr Endocrinol Metab ; 32(7): 667-674, 2019 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-31150357

RESUMEN

Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015-2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.


Asunto(s)
Biomarcadores/análisis , Aberraciones Cromosómicas , Discapacidades del Desarrollo/genética , Genómica/métodos , Discapacidad Intelectual/genética , Obesidad Pediátrica/genética , Polimorfismo de Nucleótido Simple , Adolescente , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/patología , Femenino , Estudios de Seguimiento , Pruebas Genéticas , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/patología , Masculino , Análisis por Micromatrices , Obesidad Pediátrica/complicaciones , Obesidad Pediátrica/epidemiología , Obesidad Pediátrica/patología , Pronóstico , Rumanía/epidemiología
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