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1.
Int J Mol Sci ; 25(18)2024 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-39337518

RESUMEN

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype-phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4-100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP-response-element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient's genotype for a correct diagnostic confirmation.


Asunto(s)
Receptores de Tirotropina , Disgenesias Tiroideas , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Hipotiroidismo Congénito/genética , Estudios de Asociación Genética , Genotipo , Mutación , Fenotipo , Receptores de Tirotropina/genética , Receptores de Tirotropina/metabolismo , Disgenesias Tiroideas/genética , Tirotropina/metabolismo , Tirotropina/sangre
2.
Int J Mol Sci ; 25(15)2024 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-39126042

RESUMEN

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype-phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype-phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants.


Asunto(s)
Oxidasas Duales , Estudios de Asociación Genética , Humanos , Oxidasas Duales/genética , Oxidasas Duales/metabolismo , Femenino , Masculino , Recién Nacido , Disgenesias Tiroideas/genética , Disgenesias Tiroideas/patología , Fenotipo , Mutación , Genotipo , Hipotiroidismo Congénito/genética , Tamizaje Neonatal , Tiroxina
3.
Front Endocrinol (Lausanne) ; 15: 1367808, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39040671

RESUMEN

Introduction: Defects in any thyroid hormone synthesis steps cause thyroid dyshormonogenesis (THD). THD due to thyroglobulin (TG) gene variants is a cause of congenital hypothyroidism (CH) with a wide clinical spectrum, ranging from mild to severe permanent hypothyroidism. We present high-throughput sequencing results of patients with TG variants. Methods: A CH high-throughput sequencing-panel of the main genes involved in the regulation of thyroid hormonogenesis was performed to identify those TG variants that may be related to patient THD phenotype. Results: We identified 21 TG gene variants in 19 patients (11.8%) which could explain their phenotype. Ten of those (47.6%) were not previously described. CH was biochemically severe in these 19 patients. Eight of them were reevaluated after one month of discontinuing LT4 treatment and all had severe permanent hypothyroidism. We also identified another 16 patients who presented heterozygous TG variants, of whom, at reevaluation, five had mild permanent and only one had severe permanent hypothyroidisms. Discussions: In this study, 10 novel and 11 previously reported variants in the TG gene have been identified that could explain the phenotype of 19 patients from non-consanguineous families from a large THD cohort. Although not all these TG gene variants can explain all the patients' THD phenotypes, some of them had severe or mild permanent hypothyroidism at reevaluation.


Asunto(s)
Hipotiroidismo Congénito , Tiroglobulina , Humanos , Tiroglobulina/genética , Femenino , Masculino , Hipotiroidismo Congénito/genética , Niño , Preescolar , Secuenciación de Nucleótidos de Alto Rendimiento , Fenotipo , Lactante , Disgenesias Tiroideas/genética , Mutación , Adolescente , Adulto , Recién Nacido
4.
Cells ; 13(6)2024 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-38534367

RESUMEN

We report a novel RPGR missense variant co-segregated with a familial X-linked retinitis pigmentosa (XLRP) case. The brothers were hemizygous for this variant, but only the proband presented with primary ciliary dyskinesia (PCD). Thus, we aimed to elucidate the role of the RPGR variant and other modifier genes in the phenotypic variability observed in the family and its impact on motile cilia. The pathogenicity of the variant on the RPGR protein was evaluated by in vitro studies transiently transfecting the mutated RPGR gene, and immunofluorescence analysis on nasal brushing samples. Whole-exome sequencing was conducted to identify potential modifier variants. In vitro studies showed that the mutated RPGR protein could not localise to the cilium and impaired cilium formation. Accordingly, RPGR was abnormally distributed in the siblings' nasal brushing samples. In addition, a missense variant in CEP290 was identified. The concurrent RPGR variant influenced ciliary mislocalisation of the protein. We provide a comprehensive characterisation of motile cilia in this XLRP family, with only the proband presenting PCD symptoms. The variant's pathogenicity was confirmed, although it alone does not explain the respiratory symptoms. Finally, the CEP290 gene may be a potential modifier for respiratory symptoms in patients with RPGR mutations.


Asunto(s)
Trastornos de la Motilidad Ciliar , Retinitis Pigmentosa , Humanos , Masculino , Trastornos de la Motilidad Ciliar/genética , Proteínas del Ojo/metabolismo , Genes Modificadores , Mutación , Retinitis Pigmentosa/genética
5.
J Clin Endocrinol Metab ; 108(11): e1316-e1328, 2023 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-37216904

RESUMEN

CONTEXT: Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. OBJECTIVE: This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. METHODS: Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. RESULTS: Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. CONCLUSION: The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).


Asunto(s)
Hiperinsulinismo Congénito , Diabetes Mellitus , Niño , Preescolar , Humanos , Glucemia , Automonitorización de la Glucosa Sanguínea , Hiperinsulinismo Congénito/complicaciones , Hiperinsulinismo Congénito/genética , Hiperinsulinismo Congénito/cirugía , Diabetes Mellitus/etiología , Diabetes Mellitus/genética , Hiperinsulinismo/genética , Mutación , Receptores de Sulfonilureas/genética , Pancreatectomía/efectos adversos
6.
Front Endocrinol (Lausanne) ; 13: 957969, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36303863

RESUMEN

The palmitoylation of the Hedgehog (Hh) family of morphogens, named sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH), is crucial for effective short- and long-range signaling. The hedgehog acyltransferase (HHAT) attaches the palmitate molecule to the Hh; therefore, variants in HHAT cause a broad spectrum of phenotypes. A missense HHAT novel variant c.1001T>A/p.(Met334Lys) was described in a patient first referred for a 46,XY different sexual development with partial gonadal dysgenesis but with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs. The in silico analysis of the variant predicted an affectation of the nearest splicing site. Thus, in vitro minigene studies were carried out, which demonstrated that the variant does not affect the splicing. Subsequent protein in silico studies supported the pathogenicity of the variant, and, in conclusion, this was considered the cause of the patient's phenotype.


Asunto(s)
Disgenesia Gonadal , Microcefalia , Humanos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Microcefalia/complicaciones , Microcefalia/genética , Pulgar , Desarrollo Sexual , Aciltransferasas/genética
7.
Arch Bronconeumol ; 58(1): 22-29, 2022 Jan.
Artículo en Inglés, Español | MEDLINE | ID: mdl-35249699

RESUMEN

BACKGROUND: Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain. METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019. RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47). CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

8.
J Clin Endocrinol Metab ; 106(1): e152-e170, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33029631

RESUMEN

PURPOSE: Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. PATIENTS AND METHODS: Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. RESULTS: We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. CONCLUSIONS: Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.


Asunto(s)
Hipotiroidismo Congénito/genética , Factor de Transcripción PAX8/genética , Glándula Tiroides/fisiología , Adolescente , Variación Biológica Poblacional , Niño , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/tratamiento farmacológico , Hipotiroidismo Congénito/fisiopatología , Femenino , Estudios de Seguimiento , Terapia de Reemplazo de Hormonas , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Tamizaje Neonatal , Fenotipo , Pruebas de Función de la Tiroides , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/patología , Tiroxina/uso terapéutico
9.
Arch Bronconeumol (Engl Ed) ; 57(3): 186-194, 2021 Mar.
Artículo en Inglés, Español | MEDLINE | ID: mdl-32253119

RESUMEN

INTRODUCTION: Primary ciliary dyskinesia (PCD) is characterized by an alteration in the ciliary structure causing difficulty in the clearance of respiratory secretions. Diagnosis is complex and based on a combination of techniques. The objective of this study was to design a gene panel including all known causative genes, and to corroborate their diagnostic utility in a cohort of Spanish patients. METHODS: This was a multicenter cross-sectional study of patients with a high suspicion of PCD, according to European Respiratory Society criteria, designed around a gene panel for massive sequencing using SeqCap EZ capture technology that included 44 genes associated with PCD. RESULTS: We included 79 patients, 53 of whom had a diagnosis of confirmed or highly probable PCD. The sensitivity of the gene panel was 81.1%, with a specificity of 100%. Candidate variants were found in some of the genes of the panel in 43 patients with PCD, 51.2% (22/43) of whom were homozygotes and 48.8% (21/43) compound heterozygotes. The most common causative genes were DNAH5 and CCDC39. We found 52 different variants, 36 of which were not previously described in the literature. CONCLUSIONS: The design and implementation of a tailored gene panel produces a high yield in the genetic diagnosis of PCD. This panel provides a better understanding of the causative factors involved in these patients and lays down the groundwork for future therapeutic approaches.


Asunto(s)
Síndrome de Kartagener , Estudios Transversales , Homocigoto , Humanos , Síndrome de Kartagener/diagnóstico , Mutación
10.
J Clin Med ; 9(11)2020 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-33182294

RESUMEN

Primary ciliary dyskinesia (PCD) is an autosomal recessive rare disease caused by an alteration of ciliary structure. Immunofluorescence, consisting in the detection of the presence and distribution of cilia proteins in human respiratory cells by fluorescence, has been recently proposed as a technique to improve understanding of disease-causing genes and diagnosis rate in PCD. The objective of this study is to determine the accuracy of a panel of four fluorescently labeled antibodies (DNAH5, DNALI1, GAS8 and RSPH4A or RSPH9) as a PCD diagnostic tool in the absence of transmission electron microscopy analysis. The panel was tested in nasal brushing samples of 74 patients with clinical suspicion of PCD. Sixty-eight (91.9%) patients were evaluable for all tested antibodies. Thirty-three cases (44.6%) presented an absence or mislocation of protein in the ciliary axoneme (15 absent and 3 proximal distribution of DNAH5 in the ciliary axoneme, 3 absent DNAH5 and DNALI1, 7 absent DNALI1 and cytoplasmatic localization of GAS8, 1 absent GAS8, 3 absent RSPH9 and 1 absent RSPH4A). Fifteen patients had confirmed or highly likely PCD but normal immunofluorescence results (68.8% sensitivity and 100% specificity). In conclusion, immunofluorescence analysis is a quick, available, low-cost and reliable diagnostic test for PCD, although it cannot be used as a standalone test.

11.
Front Immunol ; 10: 2325, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31681265

RESUMEN

Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Asociación Genética/métodos , Variación Genética , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Secuenciación del Exoma , Adulto Joven
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