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1.
Am J Med Genet A ; 188(6): 1777-1791, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35253369

RESUMEN

Worldwide, there are large inequalities in genetic service delivery. In 2011, we established a bi-annual joint pediatric-genetics clinic with a visiting clinical geneticist in the Dutch Caribbean. This retrospective study evaluates the yield of diagnostic testing and the clinical utility of a diagnosis for patients with rare diseases on these relatively isolated, resource-limited islands. A total of 331 patients that were referred to the clinical geneticist between November 2011 and November 2019 and had genetic testing were included in this study. A total of 508 genetic tests were performed on these patients. Microarray, next-generation sequencing gene panels, and single-gene analyses were the most frequently performed genetic tests. A molecularly confirmed diagnosis was established in 33% of patients (n = 108). Most diagnosed patients had single nucleotide variants or small insertions and/or deletions (48%) or copy number variants (34%). Molecular diagnostic yield was highest in patients referred for seizures and developmental delay/intellectual disability. The genetic diagnosis had an impact on clinical management in 52% of patients. Referrals to other health professionals and changes in therapy were the most frequently reported clinical consequences. In conclusion, despite limited financial resources, our genetics service resulted in a reasonably high molecular diagnostic yield. Even in this resource-limited setting, a genetic diagnosis had an impact on clinical management for the majority of patients. Our approach with a visiting clinical geneticist may be an example for others who are developing genetic services in similar settings.


Asunto(s)
Variaciones en el Número de Copia de ADN , Discapacidad Intelectual , Región del Caribe/epidemiología , Niño , Pruebas Genéticas/métodos , Humanos , Discapacidad Intelectual/genética , Estudios Retrospectivos
2.
Eur J Pediatr ; 176(4): 515-519, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28188379

RESUMEN

This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The c.970T>C p.(Cys324Arg) mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the laminin ß2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is considered a relatively mild variant of Pierson syndrome and is associated with later-onset (18 months) therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria, diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings. CONCLUSION: this report presents the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome. What is known • LAMB2 mutations are associated with Pierson syndrome • Pierson syndrome is associated with congenital nephrotic syndrome, microcoria and neurological deficits What is new • A novel mutation in the LAMB2 gene in two female siblings • Genotype and clinical phenotype description of a novel LAMB2 mutation.


Asunto(s)
Anomalías Múltiples/genética , Anomalías del Ojo/genética , Laminina/genética , Mutación , Insuficiencia Renal/cirugía , Niño , Preescolar , Anomalías del Ojo/patología , Femenino , Humanos , Riñón/patología , Glomérulos Renales/patología , Síndromes Miasténicos Congénitos , Nefrectomía , Síndrome Nefrótico , Fenotipo , Trastornos de la Pupila , Insuficiencia Renal/patología , Retina/diagnóstico por imagen , Retina/patología , Hermanos , Tomografía Óptica
3.
Dev Biol ; 396(2): 201-13, 2014 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-25446530

RESUMEN

UNLABELLED: Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-) ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1ß, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation. CONCLUSION: Cholangiocyte differentiation becomes progressively less dependent on NOTCH2 signaling with age, suggesting that ductal-plate formation is dependent on NOTCH2, but subsequent cholangiocyte differentiation is not.


Asunto(s)
Conductos Biliares/anomalías , Conductos Biliares/crecimiento & desarrollo , Hígado/metabolismo , Organogénesis/genética , Receptor Notch2/deficiencia , Análisis de Varianza , Animales , Cartilla de ADN/genética , Factor Nuclear 6 del Hepatocito/metabolismo , Técnicas Histológicas , Inmunohistoquímica , Ratones , Ratones Noqueados , Organogénesis/fisiología , Reacción en Cadena de la Polimerasa , Análisis de Regresión , Destete
4.
Eur J Hum Genet ; 32(4): 435-439, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38273166

RESUMEN

Verheij syndrome [VRJS; OMIM 615583] is a rare autosomal dominant neurodevelopmental disorder characterized by distinct clinical features, including growth retardation, intellectual disability, cardiac, and renal anomalies. VRJS is caused by deletions of chromosome 8q24.3 or pathogenic variants in the PUF60 gene. Recently, pathogenic PUF60 variants have been reported in some individuals with VRJS, contributing to the variability in the clinical presentation and severity of the condition. PUF60 encodes a protein involved in regulating gene expression and cellular growth. In this report, we describe a new case of VRJS with developmental delay, cardiac-, and renal abnormalities, caused by a heterozygous pathogenic PUF60 variant. Surprisingly, DNA methylation analysis revealed a pattern resembling the Cornelia de Lange syndrome (CdLS) episignature, suggesting a potential connection between PUF60 and CdLS-related genes. This case report further delineates the clinical and molecular spectrum of VRJS and supports further research to validate the interaction between VRJS and CdLS.


Asunto(s)
Síndrome de Cornelia de Lange , Discapacidad Intelectual , Humanos , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/patología , Discapacidad Intelectual/genética , Fenotipo , Proteínas de Ciclo Celular/genética
5.
Biochim Biophys Acta ; 1822(6): 988-95, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22353464

RESUMEN

The Delta-Notch pathway is an evolutionarily conserved signaling pathway which controls a broad range of developmental processes including cell fate determination, terminal differentiation and proliferation. In mammals, four Notch receptors (NOTCH1-4) and five activating canonical ligands (JAGGED1, JAGGED2, DLL1, DLL3 and DLL4) have been described. The precise function of noncanonical Notch ligands remains unclear. Delta-like 1 homolog (DLK1), the best studied noncanonical Notch ligand, has been shown to act as an inhibitor of Notch signaling in vitro, but its function in vivo is poorly understood. In this review we summarize Notch signaling during development and highlight recent studies in DLK1expression that reveal new insights into its function.


Asunto(s)
Diferenciación Celular , Desarrollo Embrionario , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Animales , Proteínas de Unión al Calcio , Proliferación Celular , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/química , Ratones , Neoplasias/metabolismo , Estructura Secundaria de Proteína
8.
Pediatr Blood Cancer ; 59(4): 743-5, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22180200

RESUMEN

Hepatoblastoma is a malignant pediatric liver tumor. The currently used diagnostic serum marker for hepatoblastoma, α-fetoprotein (AFP), is not always reliable in infants with hepatoblastoma, due to the physiologically elevated levels of AFP in this age group. In this report, we show that Delta-like 1 homolog (DLK1), a protein highly expressed during fetal development, but almost completely absent after birth, and an established liver-stem cell marker, is a new candidate serum marker of hepatoblastoma, especially in young infants.


Asunto(s)
Biomarcadores de Tumor/sangre , Hepatoblastoma/diagnóstico , Péptidos y Proteínas de Señalización Intercelular/sangre , Neoplasias Hepáticas/diagnóstico , Proteínas de la Membrana/sangre , Proteínas de Unión al Calcio , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Masculino , alfa-Fetoproteínas/análisis
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