X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report

Abstract We reported a Chinese boy with X-linked hyper IgM (XHIGM) syndrome, manifesting as recurrent and severe pneumonia caused by Pneumocystis jirovecii. His parents were healthy and unrelated. In August 2018, the 5-month-old boy manifested as cough and dyspnea, and then in July 2019, he was admitted because of the same symptoms. Immunological results of the two admissions both showed low IgG, low IgA, normal IgM and high levels of 1,3-β-D-glucan (BDG). Using next-generation sequencing (NGS), great reading counts of P. jirovecii were identified from the deep sputum in both admissions. Caspofungin combined with trimethoprim-sulfamethoxazole were used to anti-infection, and he recovered quickly. Whole-exome sequencing was performed for this family because of immune suppression, the disease-causing gene (exon 10–22 of CD40L) deletion for XHIGM syndrome was identified. NGS is beneficial for etiology diagnosis. Pneumocystis jirovecii pneumonia as an opportunistic infection could be recurrent in patients with XHIGM syndrome.

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Next generation sequencing in early diagnosis of pneumocystis jirovecii pneumonia after chemotherapy: a case report

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20193948 ◽

2019 ◽

Vol 7 (9) ◽

pp. 3561

Author(s):

Donghua Zheng ◽

Kai Chen ◽

Fang Xiao ◽

Na Liu

Keyword(s):

Case Report ◽

Next Generation Sequencing ◽

Early Stage ◽

Severe Pneumonia ◽

Pneumocystis Pneumonia ◽

Pneumocystis Jirovecii Pneumonia ◽

Next Generation ◽

Pneumocystis Jiroveci ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

The incidence of Pneumocystis pneumonia is increasing in immunosuppressive patients. How to diagnose and treat Pneumocystis pneumonia in the early stage has become an important issue for clinicians. The development of Next-generation Sequencing (NGS) provides technical support for the diagnosis of Pneumocystis pneumonia. Case report: A 14-year-old male patient was diagnosed with T lymphoblastoma and treated with chemotherapy. After chemotherapy, the patient developed bone marrow suppression and was complicated with severe pneumonia. He was given endotracheal intubation and ventilator assisted respiration. Samples of patients' alveolar lavage fluid were obtained, and Next-generation Sequencing (NGS) was used for diagnosis, confirming the pathogen as Pneumocystis jiroveci, which was treated by TMP/SMX. The patient's condition gradually improved, and was finally removed from ventilator and endotracheal tube. Pneumocystis jiroveci is a common opportunistic pathogen in immunosuppressive patients, and Next-generation Sequencing (NGS) can be used for rapid diagnosis of Pneumocystis pneumonia, thus improving the clinical therapeutic effect.

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Severe pneumonia caused by Parvimonas micra: a case report

BMC Infectious Diseases ◽

10.1186/s12879-021-06058-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qing Yu ◽

Lingling Sun ◽

Zuqing Xu ◽

Lumei Fan ◽

Yunbo Du

Keyword(s):

Bronchoalveolar Lavage Fluid ◽

Case Reports ◽

Severe Pneumonia ◽

Lavage Fluid ◽

Due Date ◽

Case Presentation ◽

Abdominal Abscesses ◽

Parvimonas Micra ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Abstract Background Parvimonas micra (P. micra) is a gram-positive anaerobic coccus that is detected widely on the skin, in the oral mucosa and in the gastrointestinal tract. In certain circumstances, P. micra can cause abdominal abscesses, bacteraemia and other infections. To the best of our knowledge, there have been no case reports describing the biological characteristics of P. micra-related pneumonia. These bacteria do not always multiply in an aerobic organ, such as the lung, and they could be easily overlooked because of the clinical mindset. Case presentation A 35-year-old pregnant woman was admitted to the emergency department 4 weeks prior to her due date who was exhibiting 5 points on the Glasgow coma scale. A computed tomography (CT) scan showed a massive haemorrhage in her left basal ganglia. She underwent a caesarean section and brain surgery before being admitted to the ICU. She soon developed severe pneumonia and hypoxemia. Given that multiple sputum cultures were negative, the patient’s bronchoalveolar lavage fluid was submitted for next-generation sequencing (NGS) to determine the pathogen responsible for the pneumonia; as a result, P. micra was determined to be the causative pathogen. Accordingly the antibiotic therapy was altered and the pneumonia improved. Conclusion In this case, we demonstrated severe pneumonia caused by the anaerobic organism P. micra, and the patient benefited from receiving the correct antibiotic. NGS was used as a method of quick diagnosis when sputum culture failed to distinguish the pathogen.

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Rare Presentation of Toxoplasma Pneumonitis in the Absence of Neurological Symptoms in an AIDS Patient and Use of Next-Generation Sequencing for Diagnosis

European Journal of Case Reports in Internal Medicine ◽

10.12890/2020_001862 ◽

2020 ◽

Author(s):

Moni Roy ◽

Nikhut Siddique ◽

Bindu Bathina ◽

Sharjeel Ahmad

Keyword(s):

Next Generation Sequencing ◽

Opportunistic Infections ◽

Miliary Tuberculosis ◽

Neurological Symptoms ◽

Pneumocystis Jirovecii Pneumonia ◽

Next Generation ◽

Rare Presentation ◽

Immunodeficiency Syndrome ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Toxoplasma gondii is a known cause of encephalitis in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients. Toxoplasma pneumonitis is a manifestation of extracerebral toxoplasmosis and can be clinically indistinguishable from other opportunistic infections including Pneumocystis jirovecii pneumonia (PJP) and miliary tuberculosis. In this case report, Toxoplasma pneumonitis and disseminated toxoplasmosis was diagnosed using next-generation sequencing (NGS) and polymerase chain reaction (PCR) assessment. NGS can detect microbial cell-free DNA (cfDNA) circulating in the plasma of over 1,000 pathogens. This case is a rare presentation of Toxoplasma pneumonitis in the absence of neurological symptoms and we discuss the use of NGS of microbial cfDNA and PCR tests that may be utilized for the timely diagnosis of such challenging cases.

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Pneumocystis jirovecii pneumonia as an initial manifestation of hyper-IgM syndrome in an infant

Medicine ◽

10.1097/md.0000000000014559 ◽

2019 ◽

Vol 98 (7) ◽

pp. e14559 ◽

Cited By ~ 2

Author(s):

Danbi Kim ◽

Ju Ae Shin ◽

Seung Beom Han ◽

Nack-Gyun Chung ◽

Dae Chul Jeong

Keyword(s):

Pneumocystis Jirovecii ◽

Pneumocystis Jirovecii Pneumonia ◽

Initial Manifestation ◽

Hyper Igm Syndrome ◽

Hyper Igm

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Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽

10.3390/genes10121047 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1047 ◽

Cited By ~ 1

Author(s):

Lama Jaffal ◽

Wissam H Joumaa ◽

Alexandre Assi ◽

Charles Helou ◽

George Cherfan ◽

...

Keyword(s):

Next Generation Sequencing ◽

Usher Syndrome ◽

Bioinformatic Analysis ◽

Next Generation ◽

Novel Mutations ◽

Pathogenic Variants ◽

Whole Exome ◽

Targeted Ngs ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

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Whole-exome sequencing and its impact in hereditary hearing loss

Genetics Research ◽

10.1017/s001667231500004x ◽

2015 ◽

Vol 97 ◽

Cited By ~ 28

Author(s):

TAHIR ATIK ◽

GUNEY BADEMCI ◽

OSCAR DIAZ-HORTA ◽

SUSAN H. BLANTON ◽

MUSTAFA TEKIN

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Deafness ◽

Whole Exome ◽

Human Genes ◽

Genetic Revolution ◽

Recent Developments ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

SummaryNext-generation sequencing (NGS) technologies have played a central role in the genetic revolution. These technologies, especially whole-exome sequencing, have become the primary tool of geneticists to identify the causative DNA variants in Mendelian disorders, including hereditary deafness. Current research estimates that 1% of all human genes have a function in hearing. To date, mutations in over 80 genes have been reported to cause nonsyndromic hearing loss (NSHL). Strikingly, more than a quarter of all known genes related to NSHL were discovered in the past 5 years via NGS technologies. In this article, we review recent developments in the usage of NGS for hereditary deafness, with an emphasis on whole-exome sequencing.

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NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

Human Genetics ◽

10.1007/s00439-021-02343-7 ◽

2021 ◽

Author(s):

I. Perea-Romero ◽

F. Blanco-Kelly ◽

I. Sanchez-Navarro ◽

I. Lorda-Sanchez ◽

S. Tahsin-Swafiri ◽

...

Keyword(s):

Exome Sequencing ◽

Diagnostic Yield ◽

A Priori ◽

Retinal Diseases ◽

Human Phenotype ◽

Whole Exome ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Clinical Category ◽

Selection Of

AbstractSyndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations.

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Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B

Endocrine Connections ◽

10.1530/ec-20-0460 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1042-1050

Author(s):

Catherine Cardot Bauters ◽

Emmanuelle Leteurtre ◽

Bruno Carnaille ◽

Christine Do Cao ◽

Stéphanie Espiard ◽

...

Keyword(s):

Germline Variant ◽

Whole Exome ◽

Familial Cancers ◽

Heterozygous Variant ◽

Unknown Significance ◽

Next Generation Sequencing Ngs ◽

Design And Methods ◽

Generation Sequencing

Objective We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis. Design and methods Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations. Results A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband. Conclusion In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.

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Progressive Myoclonus Epilepsies

Neurology Genetics ◽

10.1212/nxg.0000000000000641 ◽

2021 ◽

Vol 7 (6) ◽

pp. e641

Author(s):

Laura Canafoglia ◽

Silvana Franceschetti ◽

Antonio Gambardella ◽

Pasquale Striano ◽

Anna Teresa Giallonardo ◽

...

Keyword(s):

Late Onset ◽

Diagnostic Yield ◽

Homozygosity Mapping ◽

Genetic Origin ◽

Pathogenic Variants ◽

Whole Exome ◽

Progressive Ataxia ◽

Targeted Ngs ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

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Current Insights in Genetics of Sarcoidosis: Functional and Clinical Impacts

Journal of Clinical Medicine ◽

10.3390/jcm9082633 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2633 ◽

Cited By ~ 2

Author(s):

Alain Calender ◽

Thomas Weichhart ◽

Dominique Valeyre ◽

Yves Pacheco

Keyword(s):

Complex Disease ◽

Current Knowledge ◽

Association Studies ◽

Genetic Research ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Whole Exome ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Future Management

Sarcoidosis is a complex disease that belongs to the vast group of autoinflammatory disorders, but the etiological mechanisms of which are not known. At the crosstalk of environmental, infectious, and genetic factors, sarcoidosis is a multifactorial disease that requires a multidisciplinary approach for which genetic research, in particular, next generation sequencing (NGS) tools, has made it possible to identify new pathways and propose mechanistic hypotheses. Codified treatments for the disease cannot always respond to the most progressive forms and the identification of new genetic and metabolic tracks is a challenge for the future management of the most severe patients. Here, we review the current knowledge regarding the genes identified by both genome wide association studies (GWAS) and whole exome sequencing (WES), as well the connection of these pathways with the current research on sarcoidosis immune-related disorders.

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