A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype‐phenotype correlations

Autosomal recessive congenital ichthyoses (ARCI) have been associated with different phenotypes including: harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While pathogenic variants in all ARCI genes are associated with LI and CIE phenotypes, the unique gene associated with HI is ABCA12. In HI, the most severe ARCI form, pathogenic variants in both ABCA12 gene alleles usually have a severe impact on protein function. The presence of at least one non-truncating variant frequently causes a less severe congenital ichthyosis phenotype (LI and CIE). METHODS: We report the case of a 4-year-old Ecuadorian boy with a severe skin disease. Genetic diagnosis was performed by NGS. In silico predictions were performed using Alamut software v2.11. A review of the literature was carried out to identify all patients carrying ABCA12 splice-site and missense variants, and to explore their genotype-phenotype correlations. RESULTS: Genetic testing revealed a nonsense substitution, p.(Arg2204*), and a new missense variant, p.(Val1927Leu), in the ABCA12 gene. After performing in silico analysis and a comprehensive review of the literature, we conclude that p.(Val1927Leu) affects a well conserved residue which could either disturb the protein function or alter the splicing process, both alternatives could explain the severe phenotype of our patient. CONCLUSION: This case expands the spectrum of ABCA12 reported disease-causing variants which is important to unravel genotype-phenotype correlations and highlights the importance of missense variants in the development of HI. © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.Fundación Ramón ArecesInstituto de Salud Carlos IIIXunta de GaliciaUniversidad Espíritu Santo-Ecuado

Detección de mycobacterium tuberculosis mediante la reacción en cadena de la polimerasa en sintomáticos respiratorios, Cuenca 2009: detectar mycobacterium tuberculosis en pacientes sintomáticos respiratorios mediante PCR

Con un diseño de validación de prueba se recopilaron 100 muestras de esputo de igual número de pacientes. Se realizó baciloscopía y la prueba de RCP y se midió sensibilidad, especificidad, likelihood ratio + y likelihood ratio como análisis inherentes a la prueba en sí. Resultados. La población de estudio tuvo más mujeres (n= 55%), de ellas el 21% estuvo entre 40 y 59 años. El 65% de la muestra provino de la zona urbano. La sensibilidad de la prueba de RCP fue del 100% (IC95% 50 100), la especificidad del 72,73% (IC95% 63,4 82,01) y el Likelihood Ratio (+) del 3.6 (IC95% 2,6 5,01). No se pudo calcular el Likelihood Ratio ( ) por el valor de la sensibilidad. Discusión: la Reacción en Cadena de la Polimerasa parece tener más capacidad diagnóstica que la baciloscopía para diagnosticar la tuberculosis pulmonar y extrapulmonar. La inversión en diagnóstico permitirá ahorrar en tratamiento, es más fácil romper la cadena en un eslabón débil como la prevención y no en un eslabón difícil como el tratamientoMédicoCuenc

PLA2G6 MUTATIONS ASSOCIATED WITH A CONTINUOUS CLINICAL SPECTRUM FROM NEUROAXONAL DYSTROPHY TO HEREDITARY SPASTIC PARAPLEGIA

PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are two groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in three families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial MRI. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had two novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at four and seven years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein

Truncating mutations in UBAP1 cause hereditary spastic paraplegia

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology