RESUMEN
Pathogenic variants in surfactant proteins SP-B and SP-C cause surfactant deficiency and interstitial lung disease. Surfactant proteins are synthesized as precursors (proSP-B, proSP-C), trafficked, and processed via a vesicular-regulated secretion pathway; however, control of vesicular trafficking events is not fully understood. Through the Undiagnosed Diseases Network, we evaluated a child with interstitial lung disease suggestive of surfactant deficiency. Variants in known surfactant dysfunction disorder genes were not found in trio exome sequencing. Instead, a de novo heterozygous variant in RAB5B was identified in the Ras/Rab GTPases family nucleotide binding domain, p.Asp136His. Functional studies were performed in Caenorhabditis elegans by knocking the proband variant into the conserved position (Asp135) of the ortholog, rab-5 Genetic analysis demonstrated that rab-5[Asp135His] is damaging, producing a strong dominant negative gene product. rab-5[Asp135His] heterozygotes were also defective in endocytosis and early endosome (EE) fusion. Immunostaining studies of the proband's lung biopsy revealed that RAB5B and EE marker EEA1 were significantly reduced in alveolar type II cells and that mature SP-B and SP-C were significantly reduced, while proSP-B and proSP-C were normal. Furthermore, staining normal lung showed colocalization of RAB5B and EEA1 with proSP-B and proSP-C. These findings indicate that dominant negative-acting RAB5B Asp136His and EE dysfunction cause a defect in processing/trafficking to produce mature SP-B and SP-C, resulting in interstitial lung disease, and that RAB5B and EEs normally function in the surfactant secretion pathway. Together, the data suggest a noncanonical function for RAB5B and identify RAB5B p.Asp136His as a genetic mechanism for a surfactant dysfunction disorder.
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Variación Genética/genética , Precursores de Proteínas/genética , Proteína C Asociada a Surfactante Pulmonar/genética , Proteínas Asociadas a Surfactante Pulmonar/genética , Proteínas de Unión al GTP rab5/genética , Células Epiteliales Alveolares/metabolismo , Animales , Caenorhabditis elegans/genética , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares Intersticiales/genética , Surfactantes Pulmonares/metabolismoRESUMEN
PURPOSE: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation. METHODS: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function. RESULTS: We observed reduced LD formation, endoplasmic reticulum expansion, accumulation of aberrant lysosomes, and deficits in SREBP2 target gene expression in fibroblasts from an affected individual, indicating that the SREBF2 variant inhibits SREBP pathway activation. Using our fly model, we discovered that SREBF2 variants fail to induce LD production and act in a dominant-negative manner, which can be rescued by overexpression of S1P. CONCLUSION: Taken together, these data reveal a mechanism by which SREBF2 pathogenic variants that disrupt the S1P cleavage motif cause disease via dominant-negative antagonism of S1P, limiting the cleavage of S1P targets, including SREBP1 and SREBP2.
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Rationale: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is linked to heterozygous mutations in the FOXF1 (Forkhead Box F1) gene, a key transcriptional regulator of pulmonary vascular development. There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed. Objectives: Identify-small molecule compounds that stimulate FOXF1 signaling. Methods: We used mass spectrometry, immunoprecipitation, and the in vitro ubiquitination assay to identify TanFe (transcellular activator of nuclear FOXF1 expression), a small-molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and acute lung injury and in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV. Measurements and Main Results: We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1-HECTD1 protein-protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cells in vitro. TanFe increased protein concentrations of FOXF1 and its target genes Flk1, Flt1, and Cdh5 in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein concentrations in lungs of Foxf1+/- embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality of Foxf1+/- mice after birth. TanFe increased angiogenesis in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV with FOXF1 deletion. Conclusions: TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.
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Síndrome de Circulación Fetal Persistente , Recién Nacido , Humanos , Animales , Ratones , Síndrome de Circulación Fetal Persistente/genética , Células Endoteliales , Pulmón/metabolismo , Factores de Transcripción Forkhead/genéticaRESUMEN
Rationale: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown. Objectives: To identify cell types, gene networks, and cell-cell interactions underlying the pathogenesis of ACDMPV. Methods: We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNA in situ hybridization to identify cell types and molecular networks influenced by FOXF1 in ACDMPV lungs. Measurements and Main Results: Pathogenic single-nucleotide variants and copy-number variant deletions involving the FOXF1 gene locus in all subjects with ACDMPV (n = 6) were accompanied by marked changes in lung structure, including deficient alveolar development and a paucity of pulmonary microvasculature. Single-nucleus RNA and assay for transposase-accessible chromatin sequencing identified alterations in cell number and gene expression in endothelial cells (ECs), pericytes, fibroblasts, and epithelial cells in ACDMPV lungs. Distinct cell-autonomous roles for FOXF1 in capillary ECs and pericytes were identified. Pathogenic variants involving the FOXF1 gene locus disrupt gene expression in EC progenitors, inhibiting the differentiation or survival of capillary 2 ECs and cell-cell interactions necessary for both pulmonary vasculogenesis and alveolar type 1 cell differentiation. Loss of the pulmonary microvasculature was associated with increased VEGFA (vascular endothelial growth factor A) signaling and marked expansion of systemic bronchial ECs expressing COL15A1 (collagen type XV α 1 chain). Conclusions: Distinct FOXF1 gene regulatory networks were identified in subsets of pulmonary endothelial and fibroblast progenitors, providing both cellular and molecular targets for the development of therapies for ACDMPV and other diffuse lung diseases of infancy.
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Síndrome de Circulación Fetal Persistente , Recién Nacido , Humanos , Síndrome de Circulación Fetal Persistente/genética , Síndrome de Circulación Fetal Persistente/patología , Redes Reguladoras de Genes/genética , Factor A de Crecimiento Endotelial Vascular/genética , Células Endoteliales/patología , Multiómica , Pulmón/patología , ARN , Factores de Transcripción Forkhead/genéticaRESUMEN
PURPOSE: To describe variation in genomic medicine services across level IV neonatal intensive care units (NICUs) in the United States and Canada. METHODS: We developed and distributed a novel survey to the 43 level IV NICUs belonging to the Children's Hospitals Neonatal Consortium, requesting a single response per site from a clinician with knowledge of the provision of genomic medicine services. RESULTS: Overall response rate was 74% (32/43). Although chromosomal microarray and exome or genome sequencing (ES or GS) were universally available, access was restricted for 22% (7/32) and 81% (26/32) of centers, respectively. The most common restriction on ES or GS was requiring approval by a specialist (41%, 13/32). Rapid ES/GS was available in 69% of NICUs (22/32). Availability of same-day genetics consultative services was limited (41%, 13/32 sites), and pre- and post-test counseling practices varied widely. CONCLUSION: We observed large inter-center variation in genomic medicine services across level IV NICUs: most notably, access to rapid, comprehensive genetic testing in time frames relevant to critical care decision making was limited at many level IV Children's Hospitals Neonatal Consortium NICUs despite a significant burden of genetic disease. Further efforts are needed to improve access to neonatal genomic medicine services.
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BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes. CASE-DIAGNOSIS: We report an infant with severe renal dysplasia and lethal pulmonary hypoplasia who was homozygous for the most common BBS1 pathogenic variant (c.1169 T > G; p.M390R) and also carried a predicted pathogenic variant in TTC21B (c.1846C > T; p.R616C), a genetic modifier of disease severity of ciliopathies associated with renal dysplasia and pulmonary hypoplasia. CONCLUSIONS: This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.
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Síndrome de Bardet-Biedl , Insuficiencia Respiratoria , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación , FenotipoRESUMEN
Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.
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Retardo del Crecimiento Fetal/genética , Variación Genética/genética , Pérdida de Heterocigocidad/genética , Progeria/genética , ARN Polimerasa III/genética , Adolescente , Adulto , Alelos , Preescolar , Femenino , Genotipo , Humanos , Fenotipo , Adulto JovenRESUMEN
Chromodomain helicase DNA-binding protein 7 (CHD7) pathogenic variants are identified in more than 90% of infants and children with CHARGE (Coloboma of the iris, retina, and/or optic disk; congenital Heart defects, choanal Atresia, Retardation of growth and development, Genital hypoplasia, and characteristic outer and inner Ear anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, CHD7 sequencing and deletion/duplication analysis, SEMA3E sequencing, and trio exome and whole-genome sequencing (WGS). We used a comprehensive clinical assessment, genome-wide methylation analysis (GMA), reanalysis of WGS data, and CHD7 RNA studies to discover a novel variant that causes CHD7 haploinsufficiency. The 7-year-old Hispanic male proband has typical phenotypic features of CHARGE syndrome. GMA revealed a CHD7-associated epigenetic signature. Reanalysis of the WGS data with focused bioinformatic analysis of CHD7 detected a novel, de novo 15 base pair deletion in Intron 4 of CHD7 (c.2239-20_2239-6delGTCTTGGGTTTTTGT [NM_017780.3]). Using proband RNA, we confirmed that this novel deletion causes CHD7 haploinsufficiency by disrupting the canonical 3' splice site and introducing a premature stop codon. Integrated genomic, epigenomic, and transcriptome analyses discovered a novel CHD7 variant that causes CHARGE syndrome.
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Síndrome CHARGE/genética , Atresia de las Coanas/genética , Coloboma/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Cardiopatías Congénitas/genética , Síndrome CHARGE/complicaciones , Síndrome CHARGE/patología , Niño , Preescolar , Atresia de las Coanas/complicaciones , Atresia de las Coanas/patología , Coloboma/complicaciones , Coloboma/patología , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/patología , Humanos , Lactante , Intrones/genética , Masculino , Mutación/genética , Fenotipo , Secuenciación del ExomaRESUMEN
Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.
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Artrogriposis/genética , Proteínas Portadoras/genética , Atrofia Muscular Espinal/genética , Artrogriposis/diagnóstico por imagen , Artrogriposis/fisiopatología , Codón sin Sentido/genética , Femenino , Humanos , Recién Nacido , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/fisiopatología , Secuenciación Completa del GenomaRESUMEN
ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal neonatal respiratory distress syndrome and childhood interstitial lung disease. Qualitative functional characterization of ABCA3 missense variants suggests two pathogenic classes: disrupted intracellular trafficking (type I mutant) or impaired ATPase-mediated phospholipid transport into the lamellar bodies (type II mutant). We qualitatively compared wild-type (WT-ABCA3) with four uncharacterized ABCA3 variants (c.418A>C;p.Asn140His, c.3609_3611delCTT;p.Phe1203del, c.3784A>G;p.Ser1262Gly, and c.4195G>A;p.Val1399Met) in A549 cells using protein processing, colocalization with intracellular organelles, lamellar body ultrastructure, and ATPase activity. We quantitatively measured lamellar body-like vesicle diameter and intracellular ABCA3 trafficking using fluorescence-based colocalization. Three ABCA3 variants (p.Asn140His, p.Ser1262Gly, and p.Val1399Met) were processed and trafficked normally and demonstrated well-organized lamellar body-like vesicles, but had reduced ATPase activity consistent with type II mutants. P.Phe1203del was processed normally, had reduced ATPase activity, and well-organized lamellar body-like vesicles, but quantitatively colocalized with both endoplasmic reticulum and lysosomal markers, an intermediate phenotype suggesting disruption of both intracellular trafficking and phospholipid transport. All ABCA3 mutants demonstrated mean vesicle diameters smaller than WT-ABCA3. Qualitative and quantitative functional characterization of ABCA3 variants informs mechanisms of pathogenicity.
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Transportadoras de Casetes de Unión a ATP/genética , Células A549 , Vesículas Citoplasmáticas , Humanos , Enfermedades Pulmonares Intersticiales/genética , Mutación Missense , Alveolos Pulmonares , Surfactantes PulmonaresRESUMEN
Rare or private, biallelic variants in the ABCA3 (ATP-binding cassette transporter A3) gene are the most common monogenic cause of lethal neonatal respiratory failure and childhood interstitial lung disease. Functional characterization of fewer than 10% of over 200 disease-associated ABCA3 variants (majority missense) suggests either disruption of ABCA3 protein trafficking (type I) or of ATPase-mediated phospholipid transport (type II). Therapies remain limited and nonspecific. A scalable platform is required for functional characterization of ABCA3 variants and discovery of pharmacologic correctors. To address this need, we first silenced the endogenous ABCA3 locus in A549 cells with CRISPR/Cas9 genome editing. Next, to generate a parent cell line (A549/ABCA3-/-) with a single recombination target site for genomic integration and stable expression of individual ABCA3 missense variant cDNAs, we used lentiviral-mediated integration of a LoxFAS cassette, FACS, and dilutional cloning. To assess the fidelity of this cell-based model, we compared functional characterization (ABCA3 protein processing, ABCA3 immunofluorescence colocalization with intracellular markers, ultrastructural vesicle phenotype) of two individual ABCA3 mutants (type I mutant, p.L101P; type II mutant, p.E292V) in A549/ABCA3-/- cells and in both A549 cells and primary, human alveolar type II cells that transiently express each cDNA after adenoviral-mediated transduction. We also confirmed pharmacologic rescue of ABCA3 variant-encoded mistrafficking and vesicle diameter in A549/ABCA3-/- cells that express p.G1421R (type I mutant). A549/ABCA3-/- cells provide a scalable, genetically versatile, physiologically relevant functional genomics platform for discovery of variant-specific mechanisms that disrupt ABCA3 function and for screening of potential ABCA3 pharmacologic correctors.
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Transportadoras de Casetes de Unión a ATP/genética , Genoma/genética , Mutación Missense/genética , Células A549 , Adenosina Trifosfatasas/genética , Células Epiteliales Alveolares/metabolismo , Sistemas CRISPR-Cas/genética , Línea Celular Tumoral , ADN Complementario/genética , Técnica del Anticuerpo Fluorescente/métodos , Edición Génica/métodos , Genómica/métodos , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares Intersticiales/genéticaRESUMEN
Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients.
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Anomalías Múltiples/genética , Mama/anomalías , Anomalías Congénitas/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Predisposición Genética a la Enfermedad , Enfermedades Hematológicas/genética , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Adolescente , Adulto , Mama/diagnóstico por imagen , Mama/fisiopatología , Enfermedades de la Mama , Niño , Anomalías Congénitas/diagnóstico por imagen , Anomalías Congénitas/fisiopatología , Cara/diagnóstico por imagen , Cara/patología , Femenino , Enfermedades Hematológicas/diagnóstico por imagen , Enfermedades Hematológicas/patología , Humanos , Mutación con Pérdida de Función/genética , Masculino , Mutación/genética , Fenotipo , Enfermedades Vestibulares/diagnóstico por imagen , Enfermedades Vestibulares/patología , Secuenciación del Exoma , Adulto JovenRESUMEN
OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation. STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications. RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings. CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.
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Trasplante de Pulmón/métodos , Síndrome de Circulación Fetal Persistente/diagnóstico , Alveolos Pulmonares/anomalías , Femenino , Factores de Transcripción Forkhead/genética , Humanos , Lactante , Recién Nacido , Pulmón/patología , Masculino , Mutación , Síndrome de Circulación Fetal Persistente/complicaciones , Síndrome de Circulación Fetal Persistente/cirugía , Alveolos Pulmonares/cirugía , Venas Pulmonares/anomalías , Tasa de SupervivenciaRESUMEN
BACKGROUND: Biallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants. METHODS AND RESULTS: We performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant's fibroblasts to determine primary ciliary phenotype. RESULTS: We identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia. CONCLUSION: Biallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants.
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Encéfalo/anomalías , Proteínas Portadoras/genética , Enfermedades Cerebelosas/genética , Microcefalia/genética , Convulsiones/genética , Alelos , Encéfalo/diagnóstico por imagen , Proteínas de Ciclo Celular , Cilios , Exoma , Resultado Fatal , Fibroblastos/metabolismo , Eliminación de Gen , Variación Genética , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mutación Missense , Fenotipo , Insuficiencia RespiratoriaRESUMEN
OBJECTIVE: Preterm birth (PTB) at <37 weeks of gestation complicates 10% of pregnancies and requires accurate counseling regarding anticipated neonatal outcomes. PTB classification as spontaneous or indicated is commonly used to cluster PTB into subtypes, but whether neonatal outcomes differ by PTB subtype is unknown. We tested the hypothesis that neonatal morbidity differs based on subtype of PTB. METHODS: We performed a retrospective cohort study of live-born, non-anomalous preterm infants from 2004 to 2008. Spontaneous PTB was defined as PTB from spontaneous preterm labor or preterm rupture of membranes. Indicated PTB was defined as PTB from any maternal or fetal medical complication necessitating delivery. The primary outcome was a composite of early respiratory morbidity. Secondary outcomes included late composite respiratory morbidity and other neonatal morbidities. RESULTS: Of 1,223 preterm neonates, 60.9% were born after spontaneous PTB and 30.1% after indicated PTB. Composite early respiratory morbidity was significantly higher after indicated PTB versus spontaneous PTB (1.3, 95% confidence interval [CI] 1.2-1.4). Composite late respiratory morbidity (1.8, 95% CI 1.3-2.3) and neonatal death (2.8, 95% CI 1.5-5.1) were also significantly higher after indicated PTB versus spontaneous PTB. CONCLUSION: Neonatal respiratory outcomes and death differ according to PTB subtype. PTB subtype should be considered while counseling families and anticipating neonatal outcomes after PTB.
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Rotura Prematura de Membranas Fetales , Mortalidad Infantil , Enfermedades del Prematuro/mortalidad , Recien Nacido Prematuro , Trabajo de Parto Prematuro , Adulto , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Missouri/epidemiología , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Centros de Atención Terciaria , Adulto JovenRESUMEN
Respiratory distress syndrome (RDS) impacts a high proportion of preterm neonates, resulting in significant morbidity and mortality. Advances in pharmacotherapy, specifically antenatal corticosteroids and postnatal surfactant therapy, have significantly reduced the incidence and impact of neonatal RDS. Antenatal corticosteroids accelerate fetal lung maturation by increasing the activity of enzymes responsible for surfactant biosynthesis, resulting in improved lung compliance. Maternal antenatal corticosteroid treatment has improved survival of preterm neonates and lowered the incidence of brain injury. After birth, exogenous surfactant administration improves lung compliance and oxygenation, resulting in reductions in the incidence of pneumothorax and of death. Future research will identify the optimal surfactant product, timing of the initial dose, and mode of delivery.
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Lesiones Encefálicas , Glucocorticoides/uso terapéutico , Neumotórax , Surfactantes Pulmonares/uso terapéutico , Síndrome de Dificultad Respiratoria del Recién Nacido , Lesiones Encefálicas/etiología , Lesiones Encefálicas/prevención & control , Humanos , Recién Nacido , Recien Nacido Prematuro/fisiología , Cuidado Intensivo Neonatal/métodos , Pulmón/patología , Manejo de Atención al Paciente/métodos , Neumotórax/etiología , Neumotórax/prevención & control , Atención Prenatal/métodos , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológicoRESUMEN
Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.
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Artrogriposis/diagnóstico , Artrogriposis/genética , Genes Letales , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Fenotipo , Artrogriposis/mortalidad , Biopsia , Análisis Mutacional de ADN , Resultado Fatal , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Raíces Nerviosas Espinales/ultraestructura , Secuenciación del ExomaRESUMEN
OBJECTIVE: To compare outcomes of infants and children who underwent lung transplantation for genetic disorders of surfactant metabolism (SFTPB, SFTPC, ABCA3, and NKX2-1) over 2 epochs (1993-2003 and 2004-2015) at St Louis Children's Hospital. STUDY DESIGN: We retrospectively reviewed clinical characteristics, mortality, and short- and long-term morbidities of infants (transplanted at <1 year; n = 28) and children (transplanted >1 year; n = 16) and compared outcomes by age at transplantation (infants vs children) and by epoch of transplantation. RESULTS: Infants underwent transplantation more frequently for surfactant protein-B deficiency, whereas children underwent transplantation more frequently for SFTPC mutations. Both infants and children underwent transplantation for ABCA3 deficiency. Compared with children, infants experienced shorter times from listing to transplantation (P = .014), were more likely to be mechanically ventilated at the time of transplantation (P < .0001), were less likely to develop bronchiolitis obliterans post-transplantation (P = .021), and were more likely to have speech and motor delays (P ≤ .0001). Despite advances in genetic diagnosis, immunosuppressive therapies, and supportive respiratory and nutritional therapies, mortality did not differ between infants and children (P = .076) or between epochs. Kaplan-Meier analyses demonstrated that children transplanted in epoch 1 (1993-2003) were more likely to develop systemic hypertension (P = .049) and less likely to develop post-transplantation lymphoproliferative disorder compared with children transplanted in epoch 2 (2004-2015) (P = .051). CONCLUSION: Post-lung transplantation morbidities and mortality remain substantial for infants and children with genetic disorders of surfactant metabolism.