RESUMEN
Background and objectives: Prevalence estimates for classical homocystinuria (HCU) are variable and likely underestimated due to underdiagnosis. Claims data represent a strong but seldom used resource to analyze prevalence of HCU. The aim of this study was to estimate a prevalence range of HCU in the US utilizing a combination of diagnosis codes, total homocysteine levels, and clinical presentations indicative of HCU. Methods: This was a non-interventional retrospective cohort study, using Optum's de-identified Market Clarity Data, with a patient identification period from January 01, 2016, through September 30, 2021. An algorithm was developed to identify 2 cohorts of patients using broad and strict definitions of HCU. The index date was the date within the identification period on which the first criterion was met for the inclusion criteria. Baseline demographics, clinical characteristics, and complications were assessed and summarized using descriptive statistics. Crude and standardized prevalence estimates were calculated. Results: There were 3880 and 633 patients that met the relevant inclusion criteria for the broad and strict cohorts, respectively. The projected US prevalence of HCU was calculated to be 17,631 and 3466 based on the broad and strict definitions, respectively. The average annual standardized prevalence across 2016-2020 was 5.29 and 1.04 per 100,000 people for the broad and strict cohorts, respectively. Conclusions: Prevalence estimates of HCU vary depending on databases or datasets used and identification criteria. Many patients with clinical presentations suggesting a diagnosis of HCU did not have an associated diagnosis, potentially indicating underdiagnosis or underreporting. Future research should study alternative methods, such as the identification algorithm in our analysis, to better diagnose and understand the true prevalence of HCU.
RESUMEN
Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.
Asunto(s)
Diferenciación Celular , Sistema de Señalización de MAP Quinasas , Osteoblastos , Osteogénesis Imperfecta , Factor de Transcripción SOX9 , Animales , Femenino , Masculino , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Transgénicos , Mutación , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis/genética , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/patología , Osteogénesis Imperfecta/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Células Madre/metabolismo , Células Madre/patología , Quinasas MAP Reguladas por Señal ExtracelularRESUMEN
We completed a retrospective review of data collected by the JH-CROWN consortium based on ICD10 codes for a hospitalized cohort. The severity and prevalence of COVID-19 and development of PASC within heritable connective tissue diseases were unknown; however, clinical observation suggested a thorough examination was necessary. We compared rates of disease severity, death, and PASC in connective tissue diseases versus the entire cohort as well as in diabetes and hypertension to determine if connective tissue disease was a risk factor. Of the 15,676 patients in the database, 63 (0.40%) had a connective tissue disease, which is elevated relative to the distribution in the population, suggesting a higher risk of severe disease. Within these 63 patients, 9.52% developed PASC compared to 2.54% in the entire cohort (p < 0.005). Elucidation of populations at high risk for severe disease and development of PASC is integral to improving treatment approaches. Further, no other study to date has examined the risk in those with connective tissue diseases and these data support a need for enhanced awareness among physicians, patients, and the community.
Asunto(s)
COVID-19 , Enfermedades del Tejido Conjuntivo , Hipertensión , Humanos , SARS-CoV-2/genética , COVID-19/epidemiología , Enfermedades del Tejido Conjuntivo/epidemiología , Bases de Datos Factuales , Progresión de la EnfermedadRESUMEN
Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Discapacidad Intelectual/genética , Empalme Alternativo/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/genética , Ribonucleoproteínas Nucleares Heterogéneas/genéticaRESUMEN
Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.
Asunto(s)
Errores Innatos del Metabolismo , Humanos , Pruebas Genéticas , Fenotipo , DifosfonatosRESUMEN
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
Asunto(s)
Parálisis Cerebral/patología , Epilepsia/patología , Predisposición Genética a la Enfermedad , Variación Genética , Pérdida Auditiva/patología , Discapacidad Intelectual/patología , Espasticidad Muscular/patología , ATPasas Asociadas con Actividades Celulares Diversas/genética , Adolescente , Adulto , Alelos , Animales , Parálisis Cerebral/etiología , Parálisis Cerebral/metabolismo , Preescolar , Epilepsia/etiología , Epilepsia/metabolismo , Femenino , Pérdida Auditiva/etiología , Pérdida Auditiva/metabolismo , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/etiología , Discapacidad Intelectual/metabolismo , Masculino , Espasticidad Muscular/etiología , Espasticidad Muscular/metabolismo , Ratas , Adulto JovenRESUMEN
Hormones have traditionally been classified by their mode of biosynthetic origin. We postulate a mode of hormone biosynthesis that leads to a new subclass of protein hormones. Members of this class are derived from a cleavage event that also generates a much larger, functionally unrelated, nonhormonal protein. Here, we examine four representative members of this group: endostatin, endotrophin, asprosin, and placensin. We have named this subclass of protein hormones caudamins, from the Latin word cauda meaning 'tail'. These four caudamins have shown promise in understanding and treating diseases like metabolic syndrome and cancer. Identification of the rest of the caudamins will likely provide a plethora of drug targets for a variety of diseases.
Asunto(s)
Hormonas , HumanosRESUMEN
Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Asunto(s)
Huesos/metabolismo , Proteína Coat de Complejo I/genética , Proteína Coatómero/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Osteoporosis/genética , Animales , Ácido Ascórbico/farmacología , Huesos/efectos de los fármacos , Huesos/patología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , Proteína Coat de Complejo I/deficiencia , Proteína Coatómero/química , Proteína Coatómero/deficiencia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Embrión no Mamífero , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación del Desarrollo de la Expresión Génica , Aparato de Golgi , Haploinsuficiencia , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Osteoporosis/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Índice de Severidad de la Enfermedad , Pez CebraRESUMEN
Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis. Loss or impairment of vascular function can develop diseases, such as large bone defects, avascular necrosis, osteoporosis, osteoarthritis, and osteopetrosis. In this review, we summarize how vasculature controls bone development and homeostasis in normal and disease cases. A better understanding of this process will facilitate the development of novel disease treatments that promote bone regeneration and remodeling. Specifically, approaches based on tissue engineering components, such as stem cells and growth factors, have demonstrated the capacity to induce bone microvasculature regeneration and mineralization. This knowledge will have relevant clinical implications for the treatment of bone disorders by developing novel pharmaceutical approaches and bone grafts. Finally, the tissue engineering approaches incorporating vascular components may widely be applied to treat other organ diseases by enhancing their regeneration capacity. Impact statement Bone vasculature is imperative in the process of bone development, regeneration, and remodeling. Alterations or disruption of the bone vasculature leads to loss of bone homeostasis and the development of bone diseases. In this study, we review the role of vasculature on bone diseases and how vascular tissue engineering strategies, with a detailed emphasis on the role of stem cells and growth factors, will contribute to bone therapeutics.
Asunto(s)
Neovascularización Fisiológica , Osteogénesis , Regeneración Ósea , Huesos , MicrovasosRESUMEN
BACKGROUNDTranscriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq-guided method to diagnose individuals across a wide range of ages and clinical phenotypes.METHODSOne hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis.RESULTSThe transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts.CONCLUSIONSFor our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.TRIAL REGISTRATIONNot applicable.FUNDINGNIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development.
Asunto(s)
Fibroblastos , Enfermedades Genéticas Congénitas/genética , RNA-Seq , Piel , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , MasculinoRESUMEN
SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin-Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin-Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement.
Asunto(s)
Anomalías Múltiples/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Predisposición Genética a la Enfermedad , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Cuello/anomalías , Proteínas Nucleares/genética , Factores de Transcripción/genética , Anomalías Múltiples/epidemiología , Anomalías Múltiples/patología , Adolescente , Niño , Preescolar , Proteínas Cromosómicas no Histona/genética , Codón sin Sentido/genética , Cara/patología , Femenino , Estudios de Asociación Genética , Deformidades Congénitas de la Mano/epidemiología , Deformidades Congénitas de la Mano/patología , Humanos , Lactante , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/patología , Masculino , Micrognatismo/epidemiología , Micrognatismo/patología , Cuello/patología , FenotipoRESUMEN
There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
Asunto(s)
Anomalías Craneofaciales/genética , ADN Helicasas/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Adolescente , Adulto , Dominio Catalítico , Niño , Preescolar , Anomalías Craneofaciales/patología , ADN Helicasas/química , Discapacidades del Desarrollo/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/química , Mutación , Fenotipo , SíndromeRESUMEN
Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing â¼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Neuronas/metabolismo , Trastorno del Espectro Autista/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas , Discapacidad Intelectual/genética , Masculino , Mutación , Transporte de Proteínas/genéticaRESUMEN
EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Asunto(s)
Discapacidades del Desarrollo/genética , Variación Genética/genética , Leucoencefalopatías/genética , Malformaciones del Sistema Nervioso/genética , eIF-2 Quinasa/genética , Adolescente , Ataxia/genética , Niño , Preescolar , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Lactante , Masculino , Sustancia Blanca/patologíaRESUMEN
Worldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture-related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI-adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD (N = 98) and highest adjusted BMD (N = 110) were chosen for exome sequencing. Controls (N = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher's exact test was performed to compare low- or high-BMD subjects with controls for single-gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single-gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low-BMD subjects compared with controls (p = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low-BMD subjects compared with controls (p = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene-panel approach to screen for multivariant associations in larger cohorts. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
RESUMEN
Sudden cardiac death (SCD) is one of the leading causes of mortality in the U.S. military and competitive athletes. In this study, we simulate how genetic screening may be implemented in the military to prevent an SCD endpoint resulting from hypertrophic cardiomyopathy (HCM). We created a logistic regression model to predict variant pathogenicity in the most common HCM associated genes MYH7 and MYBPC3. Model predictions were used in conjunction with the gnomAD database to identify frequencies of pathogenic variants. Extrapolating these variants to a military population, lives saved and cost benefit analyses were conducted for screening for HCM related to pathogenic variants in MYH7 and MYBPC3. Genetic screening for HCM followed by echocardiography in individuals with pathogenic variants is predicted to save an average of 2.9 lives per accession cohort, based on historical cohort sizes, and result in a break-even cost of ~$7 per test. The false positives, defined as disqualified individuals for military service who do not have HCM, are predicted to be 0 individuals per accession cohort. This study suggests that the main barriers for the implementation of genetic screening for the U.S. military are the low detection rate and variant interpretation.
Asunto(s)
Miosinas Cardíacas/genética , Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Muerte Súbita Cardíaca/prevención & control , Cadenas Pesadas de Miosina/genética , Adulto , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/epidemiología , Muerte Súbita Cardíaca/epidemiología , Ecocardiografía/métodos , Femenino , Pruebas Genéticas , Genética de Población , Humanos , Masculino , Medicina Militar , Personal Militar , Mutación/genética , Linaje , FenotipoRESUMEN
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl-tRNA synthetase (mt-AspRS, or DARS2). While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter, brainstem, and spinal cord, the phenotypic spectrum is broad and a multitude of gene variants have been associated with the disease. Here, Dars2 disruption in CamKIIα-expressing cortical and hippocampal neurons results in slowly progressive increases in behavioral activity at five months, and culminating by nine months as severe brain atrophy, behavioral dysfunction, reduced corpus callosum thickness, and microglial morphology indicative of neuroinflammation. Interestingly, RNAseq based gene expression studies performed prior to the presentation of this severe phenotype reveal the upregulation of several pathways involved in immune activation, cytokine production and signaling, and defense response regulation. RNA transcript analysis demonstrates that activation of immune and cell stress pathways are initiated in advance of a behavioral phenotype and cerebral deficits. An understanding of these pathways and their contribution to significant neuronal loss in CamKII-Dars2 deficient mice may aid in deciphering mechanisms of LBSL pathology.
Asunto(s)
Aspartato-ARNt Ligasa/genética , Leucoencefalopatías/fisiopatología , Mitocondrias/enzimología , Animales , Atrofia , Conducta Animal , Encéfalo/patología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Corteza Cerebral/metabolismo , Cuerpo Calloso/parasitología , Hipocampo/metabolismo , Leucoencefalopatías/genética , Leucoencefalopatías/psicología , Imagen por Resonancia Magnética , Ratones , Ratones Noqueados , Neuronas/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
Asunto(s)
Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Ensamble y Desensamble de Cromatina/genética , Discapacidades del Desarrollo/genética , Femenino , Estudios de Asociación Genética , Genotipo , Pérdida Auditiva/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Masculino , Megalencefalia/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Anomalías Musculoesqueléticas/genética , Mutación Missense/genética , Fenotipo , Síndrome , Factores de Transcripción/genéticaRESUMEN
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.