scholarly journals Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients With RAG1/2 Mutations: First Cases Series From Mexico and Description of Two Novel Mutations.

2021 ◽  
Author(s):  
Mario Ernesto Cruz-Munoz ◽  
Saul Oswaldo Lugo-Reyes ◽  
Nina Pastor ◽  
Edith González-Serrano ◽  
Marco Yamazaki-Nakashimada ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Severe Combined Immunodeficiency ◽  
Clinical Manifestations ◽  
Case Series ◽  
Missense Mutations ◽  
Antigen Receptors ◽  
Novel Mutations ◽  
Nonsense Mutations ◽  
First Case ◽  
Immunological Phenotype

Abstract Mutations in Recombinase Activating Genes 1 and 2 (RAG1/2) results in human severe combined immunodeficiency (SCID). The products of these genes, are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Nonsense mutations in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with missense mutations may develop leaky SCID or Omenn syndrome (OS). A group of non-previously recognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two previously unidentified variants as causative of pathological manifestations associated to immunodeficiency. This study represents the first case series of RAG1 or RAG2 deficient patients from Mexico and Latin America.

scholarly journals IL2RG: A series of three novel mutations with clinical manifestations

2016 ◽  
Vol 3 (3) ◽  
pp. 111-118 ◽  
Author(s):  
Alisha Jamal ◽  
Julia E.M. Upton
Keyword(s):  
Nk Cells ◽  
Chart Review ◽  
Mutational Analysis ◽  
Severe Combined Immunodeficiency ◽  
Clinical Manifestations ◽  
Retrospective Chart Review ◽  
Novel Mutations ◽  
Exon 2 ◽  
Il2rg Gene ◽  
Low Levels

Background: X-linked severe combined immunodeficiency (SCID) is caused by mutations in the IL2RG gene and classically presents with absent T cells and natural killer (NK) cells. Mutational analysis has contributed to the understanding of this gene. Methods: The primary immunodeficiency (PID) registry was reviewed for patients with SCID with novel IL2RG mutations. The clinical phenotype was assessed using a retrospective chart review. Results: We describe 3 novel mutations in the IL2RG. The first was a guanine to adenine substitution at position 215 (c.215 G > A) in exon 2 leading to a cysteine to tyrosine substitution at position 72 (p.Cys72Tyr), with a typical T− B+ NK− phenotype. The second was a deletion of thymine at position 618 and adenine at position 619 (c.618_619TA) in exon 5, leading to a frameshift at the 206 amino acid (p.His206fs). The phenotype was characterized by a classic SCID presentation and immunophenotyping revealed a low number of absolute lymphocytes with mostly B cells, low levels of immunoglobulins, as well as very low NK cells. Finally, the third mutation was a guanine to cytosine substitution at position 341 (c.341 G > C) in exon 3 leading to a glycine to alanine substitution at position 114 (p.Gly114Ala), presenting with a T+ B+ NK+ phenotype. The presence of T and NK cells in IL2RG are discussed in the context of other mutations allowing for T and NK cells in IL2RG mutations, as well as in the setting of maternal engraftment. Conclusion: To the best of our knowledge we describe 3 novel mutations in the IL2RG gene and the associated phenotypes. These mutations illustrate that these patients can have atypical immunological evaluations. Statement of novelty: To the best of our knowledge, this paper describes 3 novel mutations in the IL2RG gene.

scholarly journals Fucosidosis—Clinical Manifestation, Long-Term Outcomes, and Genetic Profile—Review and Case Series

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1383 ◽  
Author(s):  
Karolina M. Stepien ◽  
Elżbieta Ciara ◽  
Aleksandra Jezela-Stanek
Keyword(s):  
Neurodegenerative Disorder ◽  
Respiratory Infections ◽  
Clinical Manifestations ◽  
Case Series ◽  
Genetic Profile ◽  
Nonsense Mutations ◽  
Pathogenic Variants ◽  
One Stop ◽  
Stop Loss

Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the FUCA1 gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described—one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype–phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases.

scholarly journals Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype

1999 ◽  
Vol 7 (3) ◽  
pp. 274-286 ◽  
Author(s):  
Karen Grønskov ◽  
Thomas Rosenberg ◽  
Annie Sand ◽  
Karen Brøndum-Nielsen
Keyword(s):  
Mutational Analysis ◽  
Missense Mutations ◽  
Novel Mutations

scholarly journals Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease

2021 ◽  
Author(s):  
Mingming Li ◽  
Jing Ma ◽  
Wenlong Wang ◽  
Xu Yang ◽  
Kaizhong Luo
Keyword(s):  
Wilson Disease ◽  
Large Scale ◽  
Allelic Frequency ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Onset Age ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Nonsense Mutations ◽  
Genotype Phenotype Correlation

Abstract AIM To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. Methods One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group.Results In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 7 mutations had not been previously reported: 1510_1511insA, 2075T>C (Leu692Pro), 2233C>A (Leu745Met), 3209C>G (Pro1070Arg),3677C>T (Thr1226Ile), 3793G>T (Val1265Leu) and 3824T>C (Leu1275Ser). The 2333G>T (Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by 2975C>T (Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The 2333G>T (Arg778 Leu) and 2975C>T (Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hot spot exons. Phenotype-genotype correlation analysis suggested that 2333G>T (Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P=0.034). 2975C>T (Pro992Leu) was correlated with earlier age of disease onset (P=0.002). Additionally, we found that the 3809A>G (Asn1270Ser) mutation significantly indicated younger onset age (P=0.012), and the 3884C>T (Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P=0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P=0.039, P=0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. Conclusion In this study, we identified seven novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

Clinical findings in five Turkish patients with citrin deficiency and identification of a novel mutation on SLC25A13

2020 ◽  
Vol 33 (1) ◽  
pp. 157-163 ◽  
Author(s):  
Melis Demir Köse ◽  
Mehtap Kagnici ◽  
Taha Reşit Özdemir ◽  
Cahit Barış Erdur ◽  
Gülin Erdemir ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Genetic Disorder ◽  
Laboratory Data ◽  
Clinical Manifestations ◽  
Case Series ◽  
Clinical Findings ◽  
First Case ◽  
Age Related ◽  
Citrin Deficiency ◽  
Turkish Patients

AbstractBackgroundCitrin deficiency (CD) is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. Three clinical manifestations have been described until today.Case presentationWe reported 5 CD patients from two families. Four patients were male and one patient was female. Two of them have NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency); three of them have CTLN2 (adult-onset type II citrullinemia). Both NICCD patients showed typical clinical and biochemical changes with a diagnosis confirmed by mutations in the SLC25A13 gene. We detected a previously unreported homozygous novel mutation c.478delC (L160Wfs*36 ) on the SLC25A13 gene. All of the CTLN2 patients were siblings. Proband was a 15-year-old mentally retarded and autistic male who had admitted to our emergency with disorientation. Laboratory data showed hyperammonemia and citrullinemia.ConclusionsTwo different profiles of age-related CD have been depicted with this article. It has been aimed to underline that the CD can be observed in different forms not only in neonatals or little infants but also in adolescents. This article is the first case series that covers both NICCD and CTLN2 cases together and that has been published in Turkey. Considering the fact that especially the majority of CTLN2 cases have been identified in Asian countries, our article has vital importance in terms of defining phenotypic features of the disease.

Diverse clinical manifestations of Cantú syndrome: The first case series in Vietnam

2021 ◽  
Author(s):  
Tu Nguyen Anh Tran ◽  
Huy Ngoc Phan ◽  
Hoang Anh Vu ◽  
Hao Trong Nguyen
Keyword(s):  
Clinical Manifestations ◽  
Case Series ◽  
First Case

scholarly journals Molecular and Clinical Insights in Malignant Brenner Tumor of the Testis With Liver Metastases:A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Pietro Parcesepe ◽  
Luigi Coppola ◽  
Andrea Remo ◽  
Mario Rosario D’Andrea ◽  
Giulia Coppola ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Ovarian Neoplasms ◽  
Mutational Analysis ◽  
Clinical Course ◽  
Molecular Testing ◽  
Missense Mutations ◽  
First Case ◽  
Brenner Tumor ◽  
Personalized Approach ◽  
Multiple Liver Metastases

Malignant Brenner Tumor (mBT) is extremely rare. Although BT are almost exclusive ovarian neoplasms, they may constitute a highly unusual tumor of the testis; in fact, only seven fully documented cases have been reported to date. Because of their rarity, the pathogenesis of these tumors has not been clarified and there is no standard therapeutic approach. We report the first case of epididymal mBT with synchronous, multiple, liver metastases and a very dramatic clinical course. Both primary tumor and metastasis were subjected to mutational analysis of 20 cancer associated genes. Primary tumor showed FGFR3 Tyr375Cys and PIK3CA His1047Arg missense mutations. Both mutations are reported as pathogenic in ClinVar database. The same FGFR3 mutation was present in liver metastasis. Based on these results we believe that the FGFR pathway could be an ideal candidate for personalized treatment, offering hope to a subset of patients with mBT. Personalized approach, including mutational analysis and molecular testing should be required in patients with rare tumors in order to clarify diagnosis and improve therapeutic strategies.

scholarly journals Novel mutation in carnitine palmitoyltransferase 1A detected through newborn screening for a presymptomatic case in China：A case report and literature review

2020 ◽  
Author(s):  
Haining Fang ◽  
Yi Gan ◽  
Fei Yu
Keyword(s):  
Newborn Screening ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Carnitine Palmitoyltransferase ◽  
Free Carnitine ◽  
Dimensional Structure ◽  
Acid Oxidation ◽  
Missense Mutations ◽  
First Case ◽  
Mitochondrial Fatty Acid

Abstract Background：Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare mitochondrial fatty acid oxidation (FAO) disorder that results in hypoketotic hypoglycemia and hepatic encephalopathy. It is caused by mutation in CPT1A. To date, only two symptomatic cases of CPT1A deficiency have been reported in China.Case presentation: A newborn male, without any disease-related clinical manifestations, was diagnosed with CPT1A deficiency through newborn screening. Increased free carnitine levels and a significantly increased C0/(C16+C18) ratio were detected at 3 days of age, and subsequently, mutations in CPT1A were found by gene sequence analysis. The patient was advised a low-fat, high-protein diet and followed up regularly. During three-years of follow-up since, the patient showed normal growth velocity and developmental milestones. Whole-exome sequencing identified two mutations, c.2201T >C (p.F734S) and c.1318G>A (p.A440T), in the patient. The c.2201T >C mutation, which has been reported previously, was inherited from his father, while the c.1318G>A, a novel mutation, was inherited from his mother. The amino acid residues encoded by original sequences are highly conserved across different species. These mutations slightly altered the three-dimensional structure of the protein, as analyzed by molecular modeling, suggesting that they may be pathogenic.Conclusion: This is the first case of CPT1A deficiency detected through newborn screening based on diagnostic levels of free carnitine, in China. We identified two missense mutations, c.2201T >C and novel c.1318G>A, in the patient. Our findings have expanded the gene spectrum of this rare condition and provided a basis for family genetic counseling and prenatal diagnosis.

scholarly journals Phenotypic and Genotypic Characterization of DEPDC5-Related Familial Focal Epilepsy: Case Series and Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Xuan Zhang ◽  
Zhaoyang Huang ◽  
Jianghong Liu ◽  
Mingyu Li ◽  
Xiaoling Zhao ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Focal Epilepsy ◽  
Clinical Manifestations ◽  
Case Series ◽  
Incomplete Penetrance ◽  
Splicing Mutation ◽  
Missense Mutations ◽  
Common Cause ◽  
Generation Sequencing

Mutations in the disheveled, Egl-10 and domain-containing protein 5 (DEPDC5) recently have been identified as a common cause of focal epilepsy syndromes. The association between phenotype and genotype of DEPDC5 mutation has not been adequately characterized. We studied four families with familial focal epilepsy carrying DEPDC5 mutations. Four novel DEPDC5 mutations were identified by next-generation sequencing, including two missense mutations (c.1729 >A and c.3260G>A), one splicing mutation (c.280-1G>A), and one frameshift mutation (c.515_516delinsT). We found that patients carrying different DEPDC5 mutation have different clinical manifestations. Incomplete penetrance is a prominent feature of DEPDC5-related epilepsy, with the rate of penetrance ranging from 25 to 100%. About 21.4% of patients with DEPDC5-related familial focal epilepsy are refractory to treatments. We further reviewed the correlation of genotype and phenotype in all previous literature regarding DEPDC5-related epilepsy. Our study suggested that the type of DEPDC5 mutation might provide important information for the prognosis evaluation.

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