-
1.
Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency.
Lu, HY, Sharma, M, Sharma, AA, Lacson, A, Szpurko, A, Luider, J, Dharmani-Khan, P, Shameli, A, Bell, PA, Guilcher, GMT, et al
The Journal of allergy and clinical immunology. 2021;(6):1559-1574.e13
Abstract
BACKGROUND Germline pathogenic variants impairing the caspase recruitment domain family member 11 (CARD11)-B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) (CBM) complex are associated with diverse human diseases including combined immunodeficiency (CID), atopy, and lymphoproliferation. However, the impact of CARD11 deficiency on human B-cell development, signaling, and function is incompletely understood. OBJECTIVES This study sought to determine the cellular, immunological, and biochemical basis of disease for 2 unrelated patients who presented with profound CID associated with viral and fungal respiratory infections, interstitial lung disease, and severe colitis. METHODS Patients underwent next-generation sequencing, immunophenotyping by flow cytometry, signaling assays by immunoblot, and transcriptome profiling by RNA-sequencing. RESULTS Both patients carried identical novel pathogenic biallelic loss-of-function variants in CARD11 (c.2509C>T; p.Arg837∗) leading to undetectable protein expression. This variant prevented CBM complex formation, severely impairing the activation of nuclear factor-κB, c-Jun N-terminal kinase, and MALT1 paracaspase activity in B and T cells. This functional defect resulted in a developmental block in B cells at the naive and type 1 transitional B-cell stage and impaired circulating T follicular helper cell (cTFH) development, which was associated with impaired antibody responses and absent germinal center structures on lymph node histology. Transcriptomics indicated that CARD11-dependent signaling is essential for immune signaling pathways involved in the development of these cells. Both patients underwent hematopoietic stem cell transplantations, which led to functional normalization. CONCLUSIONS Complete human CARD11 deficiency causes profound CID by impairing naive/type 1 B-cell and cTFH cell development and abolishing activation of MALT1 paracaspase, NF-κB, and JNK activity. Hematopoietic stem cell transplantation functionally restores impaired signaling pathways.
-
2.
Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series.
Magistrelli, L, Croce, R, De Marchi, F, Basagni, C, Carecchio, M, Nasuelli, N, Cantello, R, Invernizzi, F, Garavaglia, B, Comi, C, et al
Neurogenetics. 2021;(1):65-70
-
-
Free full text
-
Abstract
Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.
-
3.
SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review.
Remiche, G, Vandernoot, I, Sadeghi-Meibodi, N, Desmyter, L
Neurogenetics. 2021;(1):95-101
Abstract
C19orf12 gene biallelic mutations lead mainly to neurodegeneration with brain iron accumulation-4. A 15-year-old male and his 17-year-old sister complained of cramps and exercise intolerance. Clinical examination of the boy mainly showed distal amyotrophy and mild weakness, while the sister predominantly had a tetrapyramidal syndrome. Widespread chronic neurogenic signs and hypointense signals on the striatum were present in both patients. Clinical exome sequencing identified, on both patients, the compound heterozygous pathogenic mutations c.204_214del p.(Gly69ArgfsTer10) and c.32C>T p.(Thr11Met). The description of these rare SPG43 and ALS-like phenotypes in the same family contributes to improve genotype-phenotype correlation in C19orf12-related diseases.
-
4.
Rare genetic E196A mutation in a patient with Creutzfeldt-Jakob disease: a case report and literature.
Wu, X, Cui, Z, Guomin, X, Wang, H, Zhang, X, Li, Z, Sun, Q, Qi, F
Prion. 2020;(1):143-148
-
-
Free full text
-
Abstract
Genetic Creutzfeldt-Jakob disease (gCJD) is characterized by mutations in the PRNP gene and represents approximately 10-15% of the human prion diseases. Here, we report a 42-year-old Chinese man who was diagnosed with gCJD. The patient had a rare mutation in codon 196 (E196A) of PRNP leading to an exchange of amino acid from glutamic acid (E) to alanine (A). The polymorphism of codon 129 in the patient was methionine homozygote. His mother and daughter are asymptomatic carriers of the same mutation. The clinical manifestations were similar to those of sporadic CJD. 14-3-3 protein was positive in cerebrospinal fluid, and there were sharp slow complex waves in electroencephalography and ribbon-like signals on magnetic resonance imaging (MRI). The main complaints of patient changed from visual space and visual colour to psychotic symptoms with enhanced high signal intensity on the occipital and frontal cortices on MRI. We compared the clinical characteristics of the current patient with those of previously reported Chinese patients with other gCJD of E196A mutation to summarize the common features of E196A gCJD.
-
5.
Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis with Cooccurrent SF3B1 and MPL Gene Mutations: A Case Report and Brief Review of the Literature.
Park, CH, Yun, JW, Kim, HY, Lee, KO, Kim, SH, Kim, HJ
Laboratory medicine. 2020;(3):315-319
Abstract
BACKGROUND Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a new disease entity in the current WHO classification. Genetically, 60%-90% of cases have mutations in SF3B1, strongly associated with RS, and more than half of them cooccur with JAK2 V617F. This report describes the rare case of MDS/MPN-RS-T with SF3B1 mutation cooccurring with an MPL mutation. METHODS We report a 79-year-old man who was referred because of generalized edema. Peripheral blood testing showed macrocytic anemia and thrombocytosis, and bone marrow analysis demonstrated dyserythropoiesis with RS and increased megakaryocytes. A molecular study was performed to detect SF3B1 mutations and recurrent mutations in MPN disease (JAK2 V617F/exon 12, CALR gene exon 9, and MPL gene exon 10 mutations). RESULTS The molecular study revealed SF3B1 K666T and MPL W515R mutations, while BCR-ABL1 or JAK2 V617F/exon 12 and CALR mutations were all negative. CONCLUSION This is a rare case of concomitant SF3B1 and MPL mutations in MDS/MPN-RS-T.
-
6.
A Homozygotic Mutation in KDSR may Cause Keratinization Disorders and Thrombocytopenia: A Case Report.
Liu, C, Chen, XY, Wu, WQ, Zhu, XF
Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih. 2020;(3):278-282
Abstract
Pathogenic mutations in 3-keto-dihydrosphingosine reductase (KDSR) gene are associated with keratinization disorders and impaired platelet function. However, no case with both homozygotic mutation of KDSR and hepatic hemangioendothelioma has ever been reported due to its low prevalence. Here we report a seven months old Chinese boy with a homozygotic missense mutation in KDSR and both of his parents carry a same heterozygous mutation. He was born with thick plate-like scales overlying erythrodermic skin, but the skin symptoms were resolved spontaneously over the first month of his birth. He was also diagnosed with hepatic hemangioendothelioma at birth and accepted a resection surgery at 2 months old. At birth, his platelet count was severely low (10-20×109/L) with recurrent skin and gingival bleeding. Meanwhile, he suffered a mild normocytic, normochromic anemia with normal iron and hematinic levels. The anemia spontaneously recovered over the first 6 months, while the platelet count keeped at a low level (4-20×109/L). Treatment with corticosteroids, immunoglobulin or thrombopoietin was all suboptimal.
-
7.
Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review.
Abi Farraj, L, Khatoun, WD, Abou Chebel, N, Wakim, V, Dawali, K, Ghassibe-Sabbagh, M
Diagnostic pathology. 2019;(1):123
Abstract
BACKGROUND Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. CASE PRESENTATION Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. CONCLUSION Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.
-
8.
Review of SRD5A3 Disease-Causing Sequence Variants and Ocular Findings in Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation, and a Detailed New Case.
Kousal, B, Honzík, T, Hansíková, H, Ondrušková, N, Čechová, A, Tesařová, M, Stránecký, V, Meliška, M, Michaelides, M, Lišková, P
Folia biologica. 2019;(3):134-141
Abstract
Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436G>A, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome.
-
9.
UMOD gene mutations in Chinese patients with autosomal dominant tubulointerstitial kidney disease: a pediatric case report and literature review.
Yang, J, Zhang, Y, Zhou, J
BMC pediatrics. 2019;(1):145
Abstract
BACKGROUND Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD gene mutation (ADTKD-UMOD) is rare in children, characterized by hyperuricemia, gout, and progressive chronic kidney disease. It usually leads to end-stage renal failure at fiftieth decades. Here, we report a 3-year-old Chinese boy in an ADTKD family caused by a novel UMOD gene mutation. CASE PRESENTATION A 3-year-old boy was admitted to our hospital because of persistent hematuria. Urinalysis showed BLD 2+ without proteinuria. The serum levels of uric acid, creatinine and electrolytes were normal. No renal cyst or calculus was found by ultrasonography. Renal biopsy was performed and focal and segmental glomerulosclerosis was found in 4 glomeruli among 35 glomeruli examined. His father was found with end-stage renal disease (ESRD) at the age of 29, and renal ultrasound showed several cysts in both kidneys. A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was identified by whole exome sequencing in the family. SCBC Genome Browser alignment showed that V550 were highly conserved in uromodulin among different species. Software predicted that the mutation is suspected to be harmful. By literature review, there are 12 mutations of UMOD gene in 14 Chinese families including only one pediatric case(a 16-year-old girl). CONCLUSIONS A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was found in in a Chinese child case with ADTKD-UMOD, which extends our understanding of UMOD gene mutation spectrum and phenotype of ADTKD-UMOD in children.
-
10.
A CIB1 Splice-Site Founder Mutation in Families with Typical Epidermodysplasia Verruciformis.
Vahidnezhad, H, Youssefian, L, Saeidian, AH, Mansoori, B, Jazayeri, A, Azizpour, A, Hesari, KK, Yousefi, M, Zeinali, S, Jouanguy, E, et al
The Journal of investigative dermatology. 2019;(5):1195-1198