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An integrated platform for concurrent structural and single-nucleotide variants improves copy-number detection and reveals pathogenic alleles in undiagnosed Mendelian families
(Springer Science and Business Media LLC, 2025-12-31)
Haowei Du
;
Ming Yin Lun
;
Lidiia Gagarina
;
Jesse D. Bengtsson
;
Christopher M. Grochowski
1
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Clinical, immunologic, and genetic characteristics of 148 patients with natural killer cell deficiency
(Elsevier BV, 2025-05)
Manar Abdalgani
;
Evelyn R. Hernandez
;
Luis A. Pedroza
;
Ivan K. Chinn
;
Lisa R. Forbes Satter
Scopus© Citations 1 2
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Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile
(2024)
POLI HARLOWE, MARIA CECILIA BERTA
;
Boris Rebolledo-Jaramillo
;
Víctor Faundes
;
Catalina Lagos
;
Joan Orellana
<jats:title>Abstract</jats:title><jats:p>Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the “diagnostic odyssey” for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.</jats:p>
Scopus© Citations 13 6
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Genetic and Mechanistic Diversity in Hemophagocytic Lymphohistiocytosis
(2018)
Ivan K. Chinn
;
Olive S. Eckstein
;
Erin C. Peckham-Gregory
;
Baruch R. Goldberg
;
Lisa R. Forbes
1
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Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature
(2021)
Josefina Longeri Contreras
;
Mabel A. Ladino
;
Katherine Aránguiz
;
Gonzalo P. Mendez
;
Zeynep Coban-Akdemir
<jats:p>Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in <jats:italic>SLC7A7</jats:italic>. The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.</jats:p>
5Scopus© Citations 18
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Clinical, neuroimaging, and molecular spectrum of
<i>TECPR2</i>
‐associated hereditary sensory and autonomic neuropathy with intellectual disability
(2021)
Sonja Neuser
;
Barbara Brechmann
;
Gali Heimer
;
Ines Brösse
;
Susanna Schubert
25Scopus© Citations 20
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Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency
(2021)
Francesco Saettini
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POLI HARLOWE, MARIA CECILIA BERTA
;
Jaime Vengoechea
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Sonia Bonanomi
;
Julio C. Orellana
<jats:title>Abstract</jats:title> <jats:p>Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1−/− animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.</jats:p>
Scopus© Citations 28 2
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HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease
(2020)
Sarah A. Cook
;
William A. Comrie
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POLI HARLOWE, MARIA CECILIA BERTA
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Morgan Similuk
;
Andrew J. Oler
<jats:title>An inherited disorder makes WAVEs</jats:title> <jats:p> The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook <jats:italic>et al.</jats:italic> studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. </jats:p> <jats:p> <jats:italic>Science</jats:italic> , this issue p. <jats:related-article xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" issue="6500" page="202" related-article-type="in-this-issue" vol="369" xlink:href="10.1126/science.aay5663">202</jats:related-article> </jats:p>
10Scopus© Citations 94
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Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia
(2022)
Matilde I. Conte
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M. Cecilia Poli
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Angelo Taglialatela
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Giuseppe Leuzzi
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Ivan K. Chinn
9Scopus© Citations 13
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Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders
(2022)
Lisa R. Forbes
;
Olive S. Eckstein
;
Nitya Gulati
;
Erin C. Peckham-Gregory
;
Nmazuo W. Ozuah
14Scopus© Citations 15

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