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1.
Hum Mutat ; 40(12): 2318-2333, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31347739

RESUMEN

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations.


Asunto(s)
Ictiosis/genética , Ictiosis/patología , Mutación , Receptores de Superficie Celular/genética , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Línea Celular , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Linaje , Receptores de Superficie Celular/química , Análisis de Secuencia de ADN , Adulto Joven
2.
Hum Mutat ; 39(10): 1305-1313, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30011118

RESUMEN

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing.


Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Genes Recesivos , Estudios de Asociación Genética , Ictiosis/diagnóstico , Ictiosis/genética , Mutación , Alelos , Biología Computacional/métodos , Femenino , Pruebas Genéticas , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Piel/patología , Piel/ultraestructura
3.
Acta Derm Venereol ; 98(4): 437-440, 2018 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-29242947

RESUMEN

The precise classification of epidermolysis bullosa (EB) into 4 main types and more than 30 subtypes is based on the level of skin cleavage, as well as clinical and molecular features, and is crucial for early prognostication, case management, genetic counselling and prenatal or pre-implantation diagnosis. We report here the molecular pathology of 40 consecutive cases of suspected EB, which were investigated by immunofluorescence mapping (IFM) and/or by a targeted next-generation sequencing (NGS) multi-gene panel. IFM correctly established the EB subtype in 76% of cases, while the molecular pathology was completely elucidated in 90% of cases by the targeted NGS multi-gene panel. Thirteen previously unreported mutations in EB genes were identified. In cases with unclear clinical and IFM findings, mutations were found by NGS in previously unexpected genes. IFM was useful in delivering fast results in newborns, and in indicating the consequences of the variants of uncertain significance on protein level. This study underscores the efficacy of the strategy of combining targeted NGS with IFM in resolving unusual EB phenotypes. It also suggests that, despite technological advances, careful clinical evaluation and deep phenotyping remains a crucial factor that dictates successful diagnosis of EB.


Asunto(s)
Análisis Mutacional de ADN , Epidermólisis Ampollosa/diagnóstico , Epidermólisis Ampollosa/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Técnicas de Diagnóstico Molecular , Mutación , Adolescente , Adulto , Biopsia , Niño , Preescolar , Epidermólisis Ampollosa/clasificación , Epidermólisis Ampollosa/inmunología , Técnica del Anticuerpo Fluorescente , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Alemania , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Piel/inmunología , Piel/patología , Adulto Joven
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