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Protein-truncating variants (PTVs) near the 3' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.
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Epilepsia , Trastornos del Neurodesarrollo , Humanos , Estudios Retrospectivos , Mutación/genética , Epilepsia/genética , Fenotipo , Trastornos del Neurodesarrollo/genéticaRESUMEN
Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.
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Metilación de ADN , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Masculino , Femenino , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , NiñoRESUMEN
Data science methodologies can be utilized to ascertain and analyze clinical genetic data that is often unstructured and rarely used outside of patient encounters. Genetic variants from all genetic testing resulting to a large pediatric healthcare system for a 5-year period were obtained and reinterpreted utilizing the previously validated Franklin© Artificial Intelligence (AI). Using PowerBI©, the data were further matched to patients in the electronic healthcare record to associate with demographic data to generate a variant data table and mapped by ZIP codes. Three thousand and sixty-five variants were identified and 98% were matched to patients with geographic data. Franklin© changed the interpretation for 24% of variants. One hundred and fifty-six clinically actionable variant reinterpretations were made. A total of 739 Mendelian genetic disorders were identified with disorder prevalence estimation. Mapping of variants demonstrated hot-spots for pathogenic genetic variation such as PEX6-associated Zellweger Spectrum Disorder. Seven patients were identified with Bardet-Biedl syndrome and seven patients with Rett syndrome amenable to newly FDA-approved therapeutics. Utilizing readily available software we developed a database and Exploratory Data Analysis (EDA) methodology enabling us to systematically reinterpret variants, estimate variant prevalence, identify conditions amenable to new treatments, and localize geographies enriched for pathogenic variants.
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Inteligencia Artificial , Ciencia de los Datos , Humanos , Niño , Prevalencia , Pruebas Genéticas/métodos , ATPasas Asociadas con Actividades Celulares DiversasRESUMEN
Dermatologic diagnosis relies on vision primarily and auditory and verbal input secondarily. Accurate dermatologic diagnosis is predicated on seeing and perceiving a skin finding, categorizing and naming the finding correctly, and comparing the visual data and data obtained from the totality of the clinical encounter (ie, from other sensory modalities) with one's working mental database of dermatologic diagnoses. The baseline assumption-which is false-is that a dermatologist is an expert at each of the aforementioned steps and transitions sequentially between them seamlessly in an error-free fashion. Each of these steps has inherent challenges, and the transitions between steps can also be problematic. In part 1 of this 2-part report, we describe the pitfalls associated with visual recognition. In part 2, we discuss cognitive heuristics as they relate to the dermatologic diagnostic process and prevention of diagnostic error.
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Cognición/fisiología , Dermatología/métodos , Errores Diagnósticos/prevención & control , Enfermedades de la Piel/diagnóstico , Percepción Visual/fisiología , Biopsia con Aguja , Dermatólogos/psicología , Femenino , Heurística , Humanos , Inmunohistoquímica , Masculino , Enfermedades de la Piel/patologíaRESUMEN
Diagnostic error in dermatology is a large practice gap that has received little attention. Diagnosis in dermatology relies heavily on a heuristic approach that is responsible for our perception of clinical findings. To improve our diagnostic accuracy, a better understanding of the strengths and limitations of heuristics (cognitive shortcuts) used in dermatology is essential. Numerous methods have been proposed to improve diagnostic accuracy, including brain training, reducing cognitive load, and getting feedback and second opinions. Becoming comfortable with the uncertainty intrinsic to medicine is essential. Ultimately, the practice of metacognition, or thinking about how we think, can offer corrective insights to improve accuracy in diagnosis.
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Dermatólogos/psicología , Errores Diagnósticos/prevención & control , Enfermedades de la Piel/diagnóstico , Percepción Visual/fisiología , Cognición/fisiología , Dermatología/métodos , Errores Diagnósticos/psicología , Femenino , Heurística , Humanos , Masculino , Sensibilidad y EspecificidadRESUMEN
Specific mutations in MECP2 cause Rett syndrome (RTT) in females whereas other mutations in the same gene cause several other syndromes in males, including X-linked intellectual disability (with and without spasticity) (OMIM 300055) and X-linked intellectual disability due to increased dosage of MECP2 (OMIM 300260). Males can also manifest an entity known as MECP2-related severe neonatal encephalopathy whose mutations are identical to those in females with RTT. We describe here the first case of MECP2-related severe neonatal encephalopathy caused by a mutation in exon one of MECP2, a mutation rarely identified in females with RTT. © 2016 Wiley Periodicals, Inc.
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Discapacidad Intelectual/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/genética , Exones/genética , Femenino , Humanos , Recién Nacido , Discapacidad Intelectual/fisiopatología , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Mutación , Fenotipo , Síndrome de Rett/fisiopatologíaAsunto(s)
Edema/diagnóstico , Vasculitis por IgA/diagnóstico , Preescolar , Diagnóstico Diferencial , Edema/etiología , Femenino , Humanos , Vasculitis por IgA/inmunología , Vasculitis por IgA/patología , Inmunoglobulina A/sangre , Imagen por Resonancia Magnética , Piel/inmunología , Piel/patología , UrinálisisRESUMEN
Beta-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation, is caused by variants in the WDR45 gene. In this paper, we describe a patient with an atypical presentation of BPAN whose whole exome sequencing revealed a previously unattested truncating variant in the WDR45 gene (c.830+3G>C/p.Leu278Ter), the pathogenicity of which was verified by RNA transcriptomics. A number of uncommon neuroanatomic and clinical findings in our patient are discussed, expanding the phenotype associated with BPAN. This unique case challenges existing genotype-phenotype correlations and highlights the role of X chromosome skewing in shaping the clinical spectrum of BPAN.
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KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings' father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.
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Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.
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BACKGROUND The polycystic kidney and hepatic disease 1 (PKHD1) gene codes for fibrocystin-polyductin, a protein that takes part in cell-signaling for cell differentiation, especially in kidney tubules and bile ducts. A homozygous or compound heterozygous defect in this gene can cause autosomal recessive polycystic kidney disease (ARPKD). Polycystic liver disease (PCLD) can also be caused by single heterozygous variants in the PKHD1 gene. ARPKD presents with renal insufficiency and cystic dilatation of bile ducts, although disease is not expected with a single heterozygous mutation. PCLD presents with multiple cysts in the liver and dilated bile ducts as well, but with less of an impact on the kidneys than with ARPKD. Our purpose in publishing this report is to introduce an as-yet unknown variant to the body of genetic defects associated with ARPKD and PCLD, as well as to argue for the likely pathogenicity of the variant according to the prevailing criteria used for classifying gene variants. CASE REPORT We present a patient with a de novo PKHD1 variant currently classified as a variant of unknown significance manifesting with bilaterally enlarged cystic kidneys and echogenic cystic structures in the hepatic portal system, indicative of cystic disease. CONCLUSIONS Given this patient's liver and kidney presentation that does not fully align with either ARPKD or PCLD, the authors believe that the single heterozygous variant in this patient's PKHD1 gene is worthy of reporting. This new single heterozygous variant in PKHD1 gene causing cystic kidney and cystic hepatic disease in the patient should be considered 'likely pathogenic' according to the criteria set by the American College of Medical Genetics.
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Hepatopatías , Riñón Poliquístico Autosómico Recesivo , Humanos , Riñón Poliquístico Autosómico Recesivo/complicaciones , Riñón Poliquístico Autosómico Recesivo/genética , Riñón/metabolismo , Mutación , Factores de Transcripción/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismoRESUMEN
Pontocerebellar hypoplasia type 1B (PCH1B) is an autosomal recessive neurodegenerative disorder that involves hypoplasia or atrophy of the cerebellum and pons. PCH1B is caused by mutations in EXOSC3, which encodes a subunit of the RNA exosome complex. The most frequently observed mutation in PCH1B patients is a c.395A>C (p.D132A) missense variant, for which the homozygous mutation typically results in milder symptoms compared to compound heterozygous mutations or homozygous mutations for other pathogenic variants. In the present study, we report on a sibling pair harboring homozygous EXOSC3 c.395A>C missense variants who deteriorated more rapidly than previously described. These cases expand the spectrum of clinical manifestations of PCH1B associated with this variant, highlighting the need for further research to determine predictive factors of PCH1B severity.
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There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka'wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies.
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Ataxia , Canal de Potasio Kv.1.1 , Humanos , Ataxia/tratamiento farmacológico , Ataxia/genética , Activación del Canal Iónico , Canal de Potasio Kv.1.1/genética , Canal de Potasio Kv.1.1/metabolismo , Mutación , Indígena Canadiense , Medicina TradicionalRESUMEN
Episodic ataxia is an umbrella term for a group of nervous system disorders that adversely and episodically affect movement. Episodes are recurrent, characterized by loss of balance and coordination and can be accompanied by other symptoms ranging from nausea to hemiplegia. Episodic Ataxia Type 1 (EA1) is an inherited, autosomal dominant disease caused by sequence variants in KCNA1, which encodes the voltage-gated potassium channel, KCNA1 (Kv1.1). Here we report a novel loss-of-function KCNA1 pathogenic variant [c.464T>C/p.Leu155Phe] causing frequent, sudden onset of clumsiness or staggering gait in the young female proband. The gene variant was maternally inherited and the mother, whose symptoms also began in childhood, has a normal MRI and EEG, slurred speech and dystonic movements involving upper extremities and mouth. Both mother and daughter are responsive to carbamazepine. Cellular electrophysiology studies of KCNA1-L155P potassium channels revealed complete but non-dominant loss of function, with reduced current and altered gating in heterozygous channels. To our knowledge this is the first EA1-associated pathogenic variant located in the KCNA1 cytoplasmic N-terminus, expanding the reported clinically sensitive domains of the channel.
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Camptocormia, or bent-spine syndrome, is an entity with a long history and many etiologies. We discuss below both the history of this diagnosis in light of a rare case of psychogenic camptocormia and the recent changes in nosology regarding this disorder.
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Neck-Tongue Syndrome is a rare entity, and when it presents in the pediatric age group, it is usually due to osseous, ligamentous, or nervous anatomic variation. We present below a case involving a patient whose bilateral symptoms were intermittently present from the age of five to the age of twenty-one years and discuss this case in light of the present theories of the anatomic substrate underlying this syndrome.
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The pulmonary manifestations of systemic lupus erythematosus can range in severity from mild to life threatening and can be particularly marked in women who are recently postpartum. We present below a seventeen-year-old female patient, one month postpartum, who had findings consistent with an acute infectious pneumonia whom upon further query and passage of time was diagnosed with severe pneumonitis due to systemic lupus erythematosus.
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Multilevel cervical disconnection syndrome (MCDS) is a rare malformation of the cervical spine previously documented in two toddlers. We present a case of a newborn first thought to have hypoxic-ischemic encephalopathy who was subsequently diagnosed with MCDS. The possibility of in utero presentation of the syndrome in this patient and the categorization of this syndrome in the spectrum of basilar skull/upper cervical malformation syndromes is discussed.