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1.
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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2.
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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The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN-associated AMC as a type of viable fetal akinesia deformation sequence.
Mis, EK, Al-Ali, S, Ji, W, Spencer-Manzon, M, Konstantino, M, Khokha, MK, Jeffries, L, Lakhani, SA
American journal of medical genetics. Part A. 2020;(10):2291-2296
Abstract
Recessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN-associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium-related findings which appear to be recurrent in the GLDN cohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary to GLDN variants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).
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Implementation of high-resolution melting analysis of the porcupine (PORCN) gene for molecular diagnosis of focal dermal hypoplasia: Identification of a novel mutation.
Martínez-Saucedo, M, Ornelas-Fuentes, C, Dedden, M, Sánchez-Urbina, R, Díaz-García, H, Aquino-Jarquin, G, Moreno-Salgado, R, Granados-Riveron, JT
The journal of gene medicine. 2020;(5):e3165
Abstract
BACKGROUND Focal dermal hypoplasia (FDH) is rare X-linked dominant disease characterized by atrophy and linear pigmentation of the skin, split hand/foot deformities and ocular anomalies. FDH is caused by mutations of the Porcupine (PORCN) gene, which encodes an enzyme that catalyzes the palmitoylation of Wnt ligands required for their secretion. High resolution melting analysis (HRM) is a technique that allows rapid, labor-efficient, low-cost detection of genomic variants. In the present study, we report the successful implementation of HRM in the molecular diagnosis of FDH. METHODS Polymerase chain reaction and HRM assays were designed and optimized for each of the coding exons of the PORCN gene, processing genomic DNA samples form a non-affected control and a patient complying with the FDH diagnostic criteria. The causal mutation was characterized by Sanger sequencing from an amplicon showing a HRM trace suggesting heterozygous variation and was validated using an amplification-refractory mutation system (ARMS) assay. RESULTS The melting profiles suggested the presence of a variant in the patient within exon 1. Sanger sequencing revealed a previously unknown C to T transition replacing a glutamine codon for a premature stop codon at position 28, which was validated using ARMS. CONCLUSIONS Next-generation sequencing facilitates the molecular diagnosis of monogenic disorders; however, its cost-benefit ratio is not optimal when a single, small or medium size causal gene is already identified and the clinical diagnostic presumption is strong. Under those conditions, as it is the case for FDH, HRM represents a cost- and labor-effective approach.
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Altered homodimer formation and increased iron accumulation in VAC14-related disease: Case report and review of the literature.
Baumann, H, Tunc, S, Günther, A, Münchau, A, Lohmann, K, Brüggemann, N
Parkinsonism & related disorders. 2020;:41-46
Abstract
BACKGROUND Pathogenic variants in the VAC14 component of PIKFYVE complex (VAC14) gene have been identified as a cause of a childhood-onset complex dystonia with striato-nigral degeneration. VAC14 is a scaffold protein relevant for the regulation of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and is known to form homodimers. METHODS Whole exome sequencing was performed in a 32-year-old patient with adolescence-onset complex dystonia and his unaffected mother. We established primary fibroblast cultures from the patient and used stably transfected SH-SY5Y cells overexpressing wildtype or mutant VAC14 to investigate the influence of VAC14 variants on the homodimer formation. Furthermore, the current literature on VAC14-related disorders was reviewed. RESULTS Our patient presented with progressive, complex dystonia with anarthria, dysphagia, sensorineural deafness, spasticity and nigral and pallidal iron deposition and striatal hyperintensities upon MRI. We identified two rare compound-heterozygous VAC14 variants (p.Leu648Phe and p.Arg623His), both located at the C-terminus in the predicted homodimerization domain. Enhanced VAC14 homodimer formation was observed for two missense variants (p.Leu648Phe and p.Ala562Val, a published mutation), but not for p.Arg623His, compared to wildtype VAC14. In contrast to previous reports, no enlarged vacuoles were detected in fibroblasts of our patient. CONCLUSIONS We report a novel patient with a VAC14-related disorder and provide first evidence of an enhanced VAC14 homodimerization as a possible disease mechanism. Due to the increased iron deposition and the clinical overlap, this disorder should be discussed as a new form of neurodegeneration with brain iron accumulation (NBIA). We suggest that VAC14 should be implemented in NBIA gene panels.
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Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia.
Kannoth, S, Nambiar, V, Gopinath, S, Anandakuttan, A, Mathai, A, Rajan, PK
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2018;(3):455-460
Abstract
Contactin-associated protein 2 (CASPR2) antibodies are originally associated with Morvan's syndrome and peripheral nerve hyper excitability. Our objective was to study retrospectively the clinical spectrum of CASPR2 antibody-positive patients in our hospital. This is a retrospective observational study. Patients treated at the Amrita Institute of Medical Sciences from May 2013 to April 2016, who were tested positive for CASPR2 antibodies, were included. A total of 1584 samples were tested in the neuroimmunology laboratory during the study period for voltage-gated potassium channel (VGKC) complex antibodies-leucine-rich glioma-inactivated protein 1 (LGI1) and CASPR2 antibodies. Thirty-four were positive for LGI1, 13 were positive for CASPR2, and 7 were for both (total 54-3.4% positivity). Of these 54 cases, 11 were treated in our hospital. Seven were positive for LGI1, three for CASPR2, and one for both. The patient who had both CASPR2 and LGI1 antibody positive had Morvan's syndrome. One patient with CASPR2 had neuromyotonia. The other patient was admitted with status epilepticus with a syndrome of parkinsonism and ataxia. The third patient had encephalopathy and myoclonus with a syndrome of parkinsonism and ataxia. Two of them underwent siddha treatment for other ailments prior to the onset of the disease for other ailments. Our short series shows the expanding spectrum of CASPR2 autoimmunity. Syndrome of parkinsonism and ataxia is an important manifestation of CASPR2 autoimmunity where we can offer a definitive treatment.
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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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Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review.
Mordaunt, DA, Jolley, A, Balasubramaniam, S, Thorburn, DR, Mountford, HS, Compton, AG, Nicholl, J, Manton, N, Clark, D, Bratkovic, D, et al
American journal of medical genetics. Part A. 2015;(6):1330-6
Abstract
Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.
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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
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Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review.
Dwyer, JP, Sarwar, S, Egan, B, Nolan, N, Hegarty, J
Liver international : official journal of the International Association for the Study of the Liver. 2011;(10):1589-92
Abstract
Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.