Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis

Giardino, Giuliana; Gallo, Vera; Somma, Domenico; Farrow, Emily; Thiffault, Isabelle; D’Assante, Roberta; Donofrio, Vittoria; Paciolla, Mariateresa; Ursini, Matilde Valeria; Leonardi, Antonio; Saunders, Carol J.; Pignata, Claudio

doi:10.1016/j.jaci.2015.09.050

Cited by 13 publications

(5 citation statements)

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“…Specifically in this group, patient 005 was found to carry a homozygous mutation in MYD88 (c.192_194del; p.Glu66del), previously reported in several MYD88 deficiency affected families (27, 28). This patient was of a Rom ethnicity and had inherited the deletion from his unaffected consanguineous parents.…”

Section: Resultsmentioning

confidence: 51%

“…The atypical clinical presentation was responsible for the diagnostic delay. Moreover, Sanger sequencing of four candidate genes ( STAT3, ELANE, RAG1 , and RAG2 ) had given negative results (27). Homozygous mutations of DOCK8 and CLEC7A were already reported as genetic cause of two distinct PIDs, such as autosomal recessive Hyper IgE syndrome and of CMC, respectively, but never observed in a single patient.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing

et al. 2016

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BackgroundRecently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.ObjectiveTo evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.MethodsWe retrospectively analyzed genetic variants identified through targeted NGS or WES in 45 patients with complex PID of unknown etiology.ResultsForty-seven variants were identified using targeted NGS, while 5 were identified using WES. Newly identified genetic variants were classified into four groups: (I) variations associated with a well-defined PID, (II) variations associated with atypical features of a well-defined PID, (III) functionally relevant variations potentially involved in the immunological features, and (IV) non-diagnostic genotype, in whom the link with phenotype is missing. We reached a conclusive genetic diagnosis in 7/45 patients (~16%). Among them, four patients presented with a typical well-defined PID. In the remaining three cases, mutations were associated with unexpected clinical features, expanding the phenotypic spectrum of typical PIDs. In addition, we identified 31 variants in 10 patients with complex phenotype, individually not causative per se of the disorder.ConclusionNGS technologies represent a cost-effective and rapid first-line genetic approach for the evaluation of complex PIDs. WES, despite a moderate higher cost compared to targeted, is emerging as a valuable tool to reach in a timely manner, a PID diagnosis with a considerable potential to draw genotype–phenotype correlation. Nevertheless, a large fraction of patients still remains without a conclusive diagnosis. In these patients, the sum of non-diagnostic variants might be proven informative in future studies with larger cohorts of patients.

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Section: Resultsmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing

et al. 2016

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“…The second group included other three subjects in whom genetic variants were found as associated with novel phenotypic features, in previously characterized phenotypes ( Table 2). Specifically in this group, patient 005 was found to carry a homozygous mutation in MYD88 (c.192_194del; p.Glu66del), previously reported in several MYD88 deficiency affected families (27,28). This patient was of a Rom ethnicity and had inherited the deletion from his unaffected consanguineous parents.…”

Section: Additional Phenotype-based Variant Filtering Criteriamentioning

confidence: 63%

Diagnostics of Primary Immunodeficiencies Through Next Generation Sequencing

Gallo¹

2016

Preprint

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Background: Recently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome. Objective: To evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures. Methods: We retrospectively analyzed genetic variants identified through targeted NGS or WES in 45 patients with complex PID of unknown etiology. results: Forty-seven variants were identified using targeted NGS, while 5 were identified using WES. Newly identified genetic variants were classified into four groups: (I) variations associated with a well-defined PID, (II) variations associated with atypical features of a well-defined PID, (III) functionally relevant variations potentially involved in the immunological features, and (IV) non-diagnostic genotype, in whom the link with phenotype is missing. We reached a conclusive genetic diagnosis in 7/45 patients (~16%). Among them, four patients presented with a typical well-defined PID. In the remaining three cases, mutations were associated with unexpected clinical features, expanding the phenotypic spectrum of typical PIDs. In addition, we identified 31 variants in 10 patients with complex phenotype, individually not causative per se of the disorder. conclusion: NGS technologies represent a cost-effective and rapid first-line genetic approach for the evaluation of complex PIDs. WES, despite a moderate higher cost

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“…Consistently, critical COVID-19 pneumonia is both much less common and much less well understood in children than in adults. There are 15 known inborn errors of type I IFN that are recessively inherited and biochemically complete ( Meyts and Casanova, 2021 ): mutations of TLR3 ( Guo et al, 2011 ; Zhang et al, 2007 ), TICAM1 ( Sancho-Shimizu et al, 2011 ), UNC93B1 ( Casrouge et al, 2006 ), TLR7 ( Asano et al, 2021 ), IRAK4 ( Nishimura et al, 2021 ; Picard et al, 2003 ), MYD88 ( Giardino et al, 2016 ; von Bernuth et al, 2008 ), IFIH1 ( Asgari et al, 2017 ; Chen et al, 2021 ; Lamborn et al, 2017 ), TBK1 ( Schmidt et al, 2021 ; Taft et al, 2021 ), IRF7 ( Ciancanelli et al, 2015 ; Zhang et al, 2020b ), IFNAR1 ( Abolhassani et al, 2022 ; Bastard et al, 2021c ; Hernandez et al, 2019 ), IFNAR2 ( Bastard et al, 2021d ; Duncan et al, 2015 ), TYK2 ( Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ), STAT1 ( Dupuis et al, 2003 ; Le Voyer et al, 2021 ), STAT2 ( Freij et al, 2020 ; Hambleton et al, 2013 ), and IRF9 ( Bravo Garcia-Morato et al, 2019 ; Hernandez et al, 2018 ). Deficiencies of TLR3 and TRIF (encoded by TICAM1 ) disrupt the TLR3 pathway, whereas deficiencies of TLR7, MYD88, and IRAK4 affect the TLR7 pathway.…”

Section: Introductionmentioning

confidence: 99%

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

Zhang

Matuozzo

Pen

et al. 2022

Journal of Experimental Medicine

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Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5–13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10−11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

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Targeted next-generation sequencing revealed MYD88 deficiency in a child with chronic yersiniosis and granulomatous lymphadenitis

Cited by 13 publications

References 13 publications

Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing

Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing

Diagnostics of Primary Immunodeficiencies Through Next Generation Sequencing

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

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