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Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome.
García-Hernández, JL, Corchete, LA, Marcos-Alcalde, Í, Gómez-Puertas, P, Fons, C, Lazo, PA
Human genomics. 2021;(1):11
Abstract
BACKGROUND Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. METHODS To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). RESULTS The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. CONCLUSIONS Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.
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Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants.
Lipiński, P, Stawiński, P, Rydzanicz, M, Wypchło, M, Płoski, R, Stradomska, TJ, Jurkiewicz, E, Ferdinandusse, S, Wanders, RJA, Vaz, FM, et al
Journal of applied genetics. 2020;(1):87-91
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Abstract
Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene-c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.
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Malignant struma ovarii harboring a unique NRAS mutation: case report and review of the literature.
Gobitti, C, Sindoni, A, Bampo, C, Baresic, T, Giorda, G, Alessandrini, L, Canzonieri, V, Franchin, G, Borsatti, E
Hormones (Athens, Greece). 2017;(3):322-327
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Abstract
Struma ovarii (SO), a rare tumor containing at least 50% of thyroid tissue, represents approximately 5% of all ovarian teratomas; its malignant transformation rate is reported to occur in up to 10% of cases and metastases occur in about 5-6% of them. We describe a 36-year old woman who underwent laparoscopic left annessectomy two years earlier because of an ovarian cyst. Follow-up imaging revealed a right adnexal mass, ascitis and peritoneal nodes that were diagnosed as comprising a malignant SO with peritoneal secondary localizations at histopathology performed after intervention. Restaging with 18F-FDG-PET/CT scan, abdominal CT and ultrasonography showed abnormalities in the perihepatic region and presacral space and left hypochondrium localizations. The patient underwent thyroidectomy, hepatic nodulectomy and cytoreductive peritonectomy: histopathological examination did not show any malignant disease in the thyroid and confirmed the presence of peritoneal localizations due to malignant SO; molecular analysis detected NRAS Q61K mutation in exon 3, whereas no mutations were identified on the BRAF gene. The patient underwent radioiodine treatment: serum Tg was decreased at first follow-up after three months of 131I-therapy. We believe that our case raises some interesting considerations. First, pathologists should be aware of this entity and should check for the presence of point mutations suggesting an aggressive disease behavior, which could be beneficial for an optimal therapeutic approach. Second, although most of the knowledge in this field comes from case reports, efforts should be made to standardize the management of patients affected by malignant SO, including use of practice guidelines.
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A novel tri-allelic mutation of TMPRSS6 in iron-refractory iron deficiency anaemia with response to glucocorticoid.
Nie, N, Shi, J, Shao, Y, Li, X, Ge, M, Huang, J, Zhang, J, Huang, Z, Li, D, Zheng, Y
British journal of haematology. 2014;(2):300-3