RESUMEN
Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.
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Discapacidad Intelectual , Megalencefalia , Trastornos del Neurodesarrollo , Animales , Humanos , Niño , Pez Cebra/genética , Pez Cebra/metabolismo , Caenorhabditis elegans/metabolismo , Trastornos del Neurodesarrollo/genética , Discapacidad Intelectual/genética , Fenotipo , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Megalencefalia/genética , Discapacidades del Desarrollo/genética , Mutación Missense/genética , Proteínas de Unión al GTP rab5/genética , Proteínas de Unión al GTP rab5/metabolismoRESUMEN
A 5-year-old affected male had following phenotypes: autism, motor stereotypy, developmental regression, staring gaze, absent speech, and behavioral abnormality. The biochemical testing was normal and genetic testing identified a de novo pathogenic variant in ITSN1 gene in the proband. To our knowledge, this is the second report that elucidates the role of ITSN1 gene in an autosomal dominant neurodevelopmental disorder.
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Trastorno Autístico , Humanos , Masculino , Preescolar , Familia , Pruebas Genéticas , FenotipoRESUMEN
MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.
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Displasia Ectodérmica , Pruebas Genéticas , Adolescente , Femenino , Humanos , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Genotipo , Mutación , Fenotipo , SíndromeRESUMEN
SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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Proteínas Cromosómicas no Histona/genética , Discapacidades del Desarrollo/genética , Mutación Missense , Fenotipo , Proteínas Supresoras de Tumor/genética , Adolescente , Animales , Niño , Preescolar , Proteínas de Drosophila/genética , Drosophila melanogaster , Femenino , Genes Dominantes , Variación Genética , Haploinsuficiencia , Humanos , Lactante , Masculino , Microscopía Confocal , Neuroglía/metabolismo , Neuronas/metabolismo , Unión Proteica , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.
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Autofagia , Enfermedades del Desarrollo Óseo/etiología , Proteínas de Ciclo Celular/genética , Fibroblastos/patología , Fallo Hepático Agudo/etiología , Mutación , Edad de Inicio , Alelos , Secuencia de Aminoácidos , Enfermedades del Desarrollo Óseo/metabolismo , Enfermedades del Desarrollo Óseo/patología , Proteínas de Ciclo Celular/metabolismo , Niño , Preescolar , Femenino , Fibroblastos/metabolismo , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , Humanos , Lactante , Fallo Hepático Agudo/metabolismo , Fallo Hepático Agudo/patología , Masculino , Linaje , Transporte de Proteínas , Recurrencia , Homología de SecuenciaRESUMEN
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
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Anomalías Múltiples/genética , Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Variación Genética , Discapacidad Intelectual/genética , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal/genética , Adolescente , Adulto , Línea Celular , Niño , Exones/genética , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/metabolismo , Linaje , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Saccharomyces cerevisiae/metabolismoRESUMEN
PURPOSE: To describe an efficient and effective multiplex screening strategy for sulfatide degradation disorders and mucolipidosis type II/III (MLII/III) using 3â¯mL of urine. METHODS: Glycosaminoglycans were analyzed by liquid chromatography-tandem mass spectrometry. Matrix assisted laser desorption/ionization-time of flight tandem mass spectrometry was used to identify free oligosaccharides and identify 22 ceramide trihexosides and 23 sulfatides, which are integrated by 670 calculated ratios. Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) was used for post-analytical interpretation of the complex metabolite profile and to aid in the differential diagnosis of abnormal results. RESULTS: Multiplex analysis was performed on 25 sulfatiduria case samples and compiled with retrospective data from an additional 15 cases revealing unique patterns of biomarkers for each disorder of sulfatide degradation (MLD, MSD, and Saposin B deficiency) and for MLII/III, thus allowing the formulation of a novel algorithm for the biochemical diagnosis of these disorders. CONCLUSIONS: Comprehensive and integrated urine screening could be very effective in the initial workup of patients suspected of having a lysosomal disorder as it covers disorders of sulfatide degradation and narrows down the differential diagnosis in patients with elevated glycosaminoglycans.
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Glicosaminoglicanos/orina , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/orina , Mucolipidosis/diagnóstico , Sulfoglicoesfingolípidos/orina , Adolescente , Adulto , Algoritmos , Biomarcadores/orina , Niño , Preescolar , Cromatografía Liquida , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mucolipidosis/orina , Estudios Retrospectivos , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
We report a 9-year-old Chinese girl with congenital thrombotic thrombocytopenic purpura found to be a compound heterozygote for 2 pathogenic variants in the ADAMTS13 gene, including a novel variation. The girl suffered from recurrent, life-threatening episodes of thrombocytopenia and hemolysis, and laboratory testing showed ADAMST13 enzyme activity of <5%. Sequencing of the ADAMTS13 gene revealed a previously reported missense variant, c.1787C>T (p.Ala596Val), and a novel duplication defined as c.1007_1025dup19 (p.Asp343Leufs*53); the duplication is predicted to result in a premature stop codon and protein truncation. We propose that this novel variant is partly responsible for the patient's early-onset and severe phenotype.
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Proteína ADAMTS13/genética , Codón sin Sentido , Mutación Missense , Púrpura Trombocitopénica Trombótica/genética , Proteína ADAMTS13/deficiencia , Edad de Inicio , Pueblo Asiatico , Niño , Femenino , Hemólisis , Heterocigoto , Humanos , Púrpura Trombocitopénica Trombótica/patología , TrombocitopeniaRESUMEN
BACKGROUND: Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours. METHODS AND RESULTS: We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes. CONCLUSIONS: Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.
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Síndrome LEOPARD/genética , Neurofibroma/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Neoplasias de la Columna Vertebral/genética , Adolescente , Adulto , Femenino , Humanos , Hipertrofia/genética , Síndrome LEOPARD/etiología , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Neurofibroma/etiología , Neurofibromatosis 1/etiología , Neurofibromatosis 1/genética , Síndrome de Noonan/etiología , Síndrome de Noonan/genética , Neoplasias de la Columna Vertebral/etiologíaRESUMEN
Sitosterolemia is an autosomal recessive metabolic disease caused by mutations in ABCG5 or ABCG8 genes which encode for the (ATP)-binding cassette (ABC) transporters that are responsible for the trafficking of xenosterols. Liver involvement is not a recognized manifestation of this disease, and cirrhosis has been reported only once in the medical literature. We describe a fatal case of a 21-year old South Asian male who presented with decompensated cirrhosis, and biochemical abnormalities consistent with sitosterolemia. Genetic testing showed a homozygous pathogenic mutation in ABCG5, confirming the diagnosis. Sitosterolemia is a rare, but likely under-recognized condition, and a high degree of suspicion is imperative to make the diagnosis. We propose that sitosterolemia should be included in the differential diagnosis for patients with cryptogenic cirrhosis, especially as there are effective oral therapies to treat this condition. Newly diagnosed sitosterolemia patients should undergo a thorough hepatology evaluation and follow-up to evaluate for the presence, development, and progression of any hepatic involvement.
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Hipercolesterolemia/complicaciones , Enfermedades Intestinales/complicaciones , Errores Innatos del Metabolismo Lipídico/complicaciones , Cirrosis Hepática/etiología , Fitosteroles/efectos adversos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Anemia Hemolítica/etiología , Anticolesterolemiantes/uso terapéutico , Biopsia , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/etiología , Análisis Mutacional de ADN , Dieta con Restricción de Grasas , Ezetimiba/uso terapéutico , Resultado Fatal , Predisposición Genética a la Enfermedad , Herencia , Homocigoto , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Hipercolesterolemia/terapia , Enfermedades Intestinales/diagnóstico , Enfermedades Intestinales/genética , Enfermedades Intestinales/terapia , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/terapia , Lipoproteínas/genética , Cirrosis Hepática/diagnóstico , Masculino , Microscopía Electrónica , Mutación , Linaje , Fenotipo , Fitosteroles/genética , Factores de Riesgo , Resultado del Tratamiento , Xantomatosis/etiología , Adulto JovenRESUMEN
Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin-proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey.
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Síndrome de Angelman , Hermanos , Ubiquitina-Proteína Ligasas , Humanos , Síndrome de Angelman/genética , Síndrome de Angelman/diagnóstico , Femenino , Ubiquitina-Proteína Ligasas/genética , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Fenotipo , Linaje , Mutación , Niño , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Predisposición Genética a la Enfermedad , PreescolarRESUMEN
BACKGROUND: To date, almost 600 genes have been associated with ocular genetic diseases. As these discoveries are made, clinical genetic testing continues to grow and become a more common element in the diagnostic workup of children with blindness and reduced vision. However, few studies have explored the motivations of parents of pediatric patients for pursuing genetic testing or the topics they would like to discuss during their visit. This study explored these gaps in the existing knowledge of clinical care for children with vision loss. MATERIALS AND METHODS: We distributed a REDCap survey to parents of pediatric patients in the Indiana University Ocular Genetics Clinic and through the Foundation Fighting Blindness MyRetinaTracker database to examine factors that motivate families to undergo genetic testing, topics they are interested in discussing, and satisfaction with their current care. RESULTS: Parents were primarily motivated by the opportunity to learn about their child's prognosis, formal diagnosis, and possible treatment options. Parents were most interested in discussing prognosis, adaptations for vision loss, and testing logistics. Parents reported satisfaction with the care received; however, less than half were very satisfied with their understanding of prognosis and the support resources provided. CONCLUSIONS: Parents seem to be generally satisfied by the care from their ocular genetics team. However, families' desires are not being fully met, especially with information about prognosis and support resources. As the field of ocular genetics continues to grow, it is important we improve these offerings and optimize care for this patient population.
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Motivación , Padres , Humanos , Niño , Pruebas Genéticas , Encuestas y Cuestionarios , Trastornos de la Visión , CegueraRESUMEN
Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and a SAMD9 germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.
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Deleción Cromosómica , Síndromes Mielodisplásicos , Femenino , Humanos , Mutación de Línea Germinal , Péptidos y Proteínas de Señalización Intracelular/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Fenotipo , AdolescenteRESUMEN
IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 mo of age with a history of IUGR, poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole-exome sequencing revealed a novel c.1464T > G p.(Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in the URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF-1 level consistent with abnormal IGF-1 receptor function. Workup resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing, and familial segregation studies through the URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.
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Microcefalia , Enfermedades Raras , Anomalías Múltiples , Estudios de Factibilidad , Femenino , Retardo del Crecimiento Fetal/genética , Trastornos del Crecimiento/genética , Heterocigoto , Humanos , Microcefalia/genética , Embarazo , Receptor IGF Tipo 1/genéticaRESUMEN
Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.
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Polidactilia , Síndrome de Costilla Pequeña y Polidactilia , Femenino , Humanos , Recién Nacido , Embarazo , Dineínas Citoplasmáticas/genética , Secuenciación del Exoma , Mutación , Costillas , ARN Mensajero , Síndrome de Costilla Pequeña y Polidactilia/diagnóstico , Síndrome de Costilla Pequeña y Polidactilia/genéticaRESUMEN
Endurance training has been associated with increased orthostatic intolerance. The purpose of the present study was to test the hypothesis that endurance training reduces renal vasoconstriction to orthostatic stress. Blood pressure, heart rate, and renal blood flow velocity were measured during a 25-min 60 degrees head-up tilt (HUT) test before and after 8 wk of endurance training in eight healthy sedentary subjects (26 +/- 1 yrs). Training elicited a 21 +/- 3% increase in peak oxygen uptake (V(O(2)peak)) and a reduction in heart rate at rest of 8 +/- 2 beats/min. During HUT, heart rate progressively increased (approximately 20 beats/min) over the 25-min HUT trial both before and after training. Systolic arterial blood pressure during HUT was unchanged with training, whereas diastolic arterial blood pressure was lower at the end of HUT after training. Before training renal blood flow velocity (Delta14 +/- 5 cm/s) and renal vascular conductance (Delta22 +/- 7%) decreased during HUT, whereas after training renal blood flow velocity (Delta2 +/- 5 cm/s) and renal vascular conductance (Delta1 +/- 12%) did not change significantly during HUT. Renal blood flow velocity and vascular conductance responses to HUT did not change in control subjects during the 8-wk period. These results demonstrate that endurance training reduces renal vasoconstriction during an orthostatic challenge and may contribute to training-induced orthostatic intolerance.
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Riñón/irrigación sanguínea , Intolerancia Ortostática/fisiopatología , Educación y Entrenamiento Físico , Resistencia Física , Vasoconstricción , Adulto , Ciclismo , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Consumo de Oxígeno , Carrera , Pruebas de Mesa InclinadaRESUMEN
We report on a 12-year-old female with both a partial duplication and deletion involving chromosome 6. The duplication involves 6p25.3p24.3 (7.585 Mb) while the deletion includes 6q27q27 (6.244 Mb). This chromosomal abnormality is also described as distal trisomy 6p and distal monosomy 6q. The patient has a Chiari II malformation, hydrocephalus, agenesis of the corpus callosum, microcephaly, bilateral renal duplicated collecting system, scoliosis, and myelomeningocele associated with a neurogenic bladder and bladder reflux. Additional features have included seizures, feeding dysfunction, failure to thrive, sleep apnea, global developmental delay, intellectual disability, and absent speech. To our knowledge, our report is just the sixth case in the literature with concomitant distal 6p duplication and distal 6q deletion. Although a majority of chromosomal duplication-deletion cases have resulted from a parental pericentric inversion, the parents of our case have normal chromosomes. This is the first reported de novo case of distal 6p duplication and distal 6q deletion. Alternate explanations for the origin of the patient's chromosome abnormalities include parental gonadal mosaicism, nonallelic homologous recombination, or potentially intrachromosomal transposition of the telomeres of chromosome 6. Nonpaternity was considered but ruled out by whole exome sequencing analysis.
RESUMEN
Fibrolamellar hepatocellular carcinoma (fHCC) is a rare primary liver cancer that affects young adults with no prior liver disease. fHCC-associated hyperammonemic encephalopathy (HAE) is an uncommon and life-threatening complication. Hyperammonemia has been reported in both typical and fHCC as a result of intrahepatic shunting, side effect from immunotherapy or chemotherapy, or as a paraneoplastic phenomenon. We present a case of a 32-year-old woman with recurrent metastatic fHCC who developed HAE in the setting of steroid administration. Her hyperammonemia was exacerbated by steroid-induced protein catabolism. She was treated with ammonia scavenging medications, a low protein diet, and was placed on chronic ammonia scavenger therapy while undergoing chemotherapy. In this case report, we discuss the proposed mechanisms of HAE, and we review the literature regarding clinical presentation and treatment.
RESUMEN
BACKGROUND: We describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas. METHODS: The patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation-dependent probe amplification and trio-based exome sequencing. Subsequently, research-based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype. RESULTS: Clinical exome sequencing of patient and parent samples revealed a maternally inherited splice-site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation-dependent probe amplification. Whole transcriptome sequencing identified a SAMD12-EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re-review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion-causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologies CONCLUSIONS: While mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.