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1.
Genet Med ; 22(5): 878-888, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31949314

RESUMEN

PURPOSE: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). METHODS: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. RESULTS: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. CONCLUSIONS: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.


Asunto(s)
Discapacidad Intelectual , Megalencefalia , Trastornos del Neurodesarrollo , Niño , Femenino , Factores de Transcripción GATA/genética , Humanos , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Nucleosomas , Fenotipo , Embarazo , Proteínas Represoras
3.
Am J Med Genet A ; 167A(10): 2231-7, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26079862

RESUMEN

De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate-to-severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide-based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 Wiley Periodicals, Inc.


Asunto(s)
Heterocigoto , Discapacidad Intelectual/genética , Mutación , Proteínas Activadoras de ras GTPasa/genética , Adolescente , Niño , Preescolar , Estreñimiento/diagnóstico , Estreñimiento/genética , Estreñimiento/patología , Análisis Mutacional de ADN , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/patología , Femenino , Trastornos Neurológicos de la Marcha/diagnóstico , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/patología , Expresión Génica , Haploinsuficiencia , Luxación de la Cadera/diagnóstico , Luxación de la Cadera/genética , Luxación de la Cadera/patología , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Fenotipo , Estrabismo/diagnóstico , Estrabismo/genética , Estrabismo/patología , Gemelos Monocigóticos
5.
J Clin Invest ; 127(5): 1700-1713, 2017 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-28346228

RESUMEN

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.


Asunto(s)
Insuficiencia Suprarrenal/congénito , Deleción Cromosómica , Mutación del Sistema de Lectura , Haploinsuficiencia , Síndromes Mielodisplásicos/genética , Proteínas/genética , Insuficiencia Suprarrenal/genética , Insuficiencia Suprarrenal/mortalidad , Cromosomas Humanos Par 7 , Estudios de Cohortes , Mutación del Sistema de Lectura/genética , Humanos , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular , Masculino , Síndromes Mielodisplásicos/mortalidad
6.
Arthritis Rheum ; 48(9): 2632-44, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-13130484

RESUMEN

OBJECTIVE: To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. METHODS: Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. RESULTS: Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. CONCLUSION: The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.


Asunto(s)
Antígenos CD/genética , Fiebre Mediterránea Familiar/genética , Heterogeneidad Genética , Periodicidad , Receptores del Factor de Necrosis Tumoral/genética , Antígenos CD/sangre , Salud de la Familia , Femenino , Citometría de Flujo , Efecto Fundador , Expresión Génica , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Fenotipo , Regiones Promotoras Genéticas/genética , Receptores del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral
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