RESUMEN
BACKGROUND: Arterial tortuosity syndrome is a rare Autosomal recessive disease that leads to a loss of function of the connective tissues of the body, this happens due to a mutation in the solute carrier family 2 member 10 (SLC2A10) gene. ATS is more likely to occur in Large and medium-sized arteries including the aorta and pulmonary arteries. This syndrome causes the arteries to be elongated and tortuous, This tortuosity disturbs the blood circulation resulting in stenosis and lack of blood flow to organs and this chronic turbulent flow increases the risk of aneurysm development, dissection and ischemic events. CASE PRESENTATION: A 2 years old Arabian female child was diagnosed with ATS affecting the pulmonary arteries as a newborn, underwent a pulmonary arterial surgical reconstruction at the age of 2 years old due to the development of pulmonary artery stenosis with left pulmonary artery having a peak gradient of 73 mmHg with a peak velocity of 4.3 m/s and the right pulmonary artery having a peak gradient of 46 mmHg with a peak velocity of 3.4 m/s causing right ventricular hypertension. After surgical repair the left pulmonary artery has a peak pressure gradient of 20 mmHg, with the right pulmonary artery having a peak pressure gradient of 20 mmHg. CONCLUSION: ATS is a rare genetic condition that affects the great arteries especially the pulmonary arteries causing stenotic and tortuous vessels that may be central branches or distal peripheral branches that leads to severe right ventricular dysfunction and hypertension. We believe that surgical treatment provides the optimum outcomes when compared to transcather approaches especially when the peripheral arteries are involved. Some challenges and hiccups might occur, especially lung reperfusion injury that needs to be diagnosed and treated accordingly.
Asunto(s)
Arteria Pulmonar , Enfermedades Cutáneas Genéticas , Malformaciones Vasculares , Humanos , Arteria Pulmonar/cirugía , Arteria Pulmonar/anomalías , Femenino , Malformaciones Vasculares/cirugía , Malformaciones Vasculares/complicaciones , Preescolar , Enfermedades Cutáneas Genéticas/cirugía , Enfermedades Cutáneas Genéticas/complicaciones , Enfermedades Cutáneas Genéticas/genética , Procedimientos Quirúrgicos Vasculares/métodos , Estenosis de Arteria Pulmonar/cirugía , Inestabilidad de la Articulación/cirugía , Inestabilidad de la Articulación/genética , Procedimientos de Cirugía Plástica/métodos , Arterias/anomalíasRESUMEN
The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.
Asunto(s)
Matriz Extracelular , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/genética , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/congénito , N-Metiltransferasa de Histona-Lisina/genética , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/patología , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Aneurisma de la Aorta/genética , Mutación , Proteínas de Unión al ADN/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/patología , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Anomalías del Ojo , Anomalías CutáneasRESUMEN
ARID1B-related disorders constitute a clinical continuum, from classic Coffin-Siris syndrome to intellectual disability (ID) with or without nonspecific dysmorphic features. Here, we describe an 11-year-old boy with an ARID1B mutation whose phenotype changed from severe developmental delay and ID to a complex neurodevelopmental disorder with multidimensional impairments, including normal intelligence despite heterogeneous IQ scores, severe motor coordination disorder, oral language disorder and attention-deficit/hyperactivity disorder. Phenotypic changes occurred after early intensive remediation and paralleled the normalization of myelination impairments, as evidenced by early brain imaging. WHAT THIS PAPER ADDS?: This report describes a 10-year multidisciplinary follow-up of a child with an ARID1B mutation who received early intensive remediation and whose phenotype changed during development. Clinical improvement paralleled the normalization of myelination impairments. This case supports a dimensional approach for complex neurodevelopmental disorders.
Asunto(s)
Proteínas de Unión al ADN , Discapacidad Intelectual , Micrognatismo , Fenotipo , Factores de Transcripción , Humanos , Masculino , Niño , Discapacidad Intelectual/genética , Factores de Transcripción/genética , Proteínas de Unión al ADN/genética , Micrognatismo/genética , Micrognatismo/diagnóstico por imagen , Estudios de Seguimiento , Cara/anomalías , Cara/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/anomalías , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/diagnóstico por imagen , Cuello/anomalías , Cuello/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/genética , Imagen por Resonancia Magnética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Discapacidades del Desarrollo/genética , Trastornos de la Destreza Motora/genética , Mutación , Deformidades Congénitas del Pie/genética , Deformidades Congénitas del Pie/diagnóstico por imagen , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/genéticaRESUMEN
Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.
Asunto(s)
Quimiocina CCL3 , Vía de Señalización Hippo , Degeneración del Disco Intervertebral , Vértebras Lumbares , Osteoclastos , Transducción de Señal , Degeneración del Disco Intervertebral/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/genética , Animales , Osteoclastos/metabolismo , Osteoclastos/patología , Vértebras Lumbares/patología , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Ratones , Cartílago/patología , Cartílago/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Inestabilidad de la Articulación/patología , Inestabilidad de la Articulación/genética , Condrocitos/metabolismo , Condrocitos/patología , Proteínas Señalizadoras YAP/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
Meier-Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, and is caused by pathogenic variants of cellular factors involved in the initiation of DNA replication. We previously reported that biallelic variants in GINS3 leading to amino acid changes at position 24 (p.Asp24) cause MGORS. Here, we describe the phenotype of a new individual homozygous for the Asp24Asn variant. We also report the clinical characteristics of an individual harboring a novel homozygous GINS3 variant (Ile25Phe) and features suggestive of MGORS. Modification of the corresponding residue in yeast Psf3 (Val9Phe) compromised S phase progression compared to a humanized Psf3 Val9Ile variant. Expression of Psf3 Val9Phe in yeast also caused sensitivity to elevated temperature and the replicative stress-inducing drug hydroxyurea, confirming partial loss of function of this variant in vivo and allowing us to upgrade the classification of this variant. Taken together, these data validate the critical importance of the GINS DNA replication complex in the molecular etiology of MGORS.
Asunto(s)
Microtia Congénita , Rótula , Humanos , Microtia Congénita/genética , Rótula/anomalías , Rótula/patología , Micrognatismo/genética , Fenotipo , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Masculino , Femenino , Saccharomyces cerevisiae/genética , Mutación , Replicación del ADN/genética , Nariz/anomalías , Nariz/patología , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/patología , Homocigoto , Proteínas Cromosómicas no Histona/genética , NiñoRESUMEN
Ehlers-Danlos syndromes (EDSs) constitute a heterogeneous group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Asymptomatic EDSs, joint hypermobility without associated syndromes, EDSs, and hypermobility spectrum disorders are the commonest phenotypes associated with joint hypermobility. Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by extreme flexibility of the joints, along with pain and other symptoms. JHS can be a sign of a more serious underlying genetic condition, such as EDS, which affects the cartilage, bone, fat, and blood. The exact cause of JHS could be related to genetic changes in the proteins that add flexibility and strength to the joints, ligaments, and tendons, such as collagen. Membrane proteins are a class of proteins embedded in the cell membrane and play a crucial role in cell signaling, transport, and adhesion. Dysregulated membrane proteins have been implicated in a variety of diseases, including cancer, cardiovascular disease, and neurological disorders; recent studies have suggested that membrane proteins may also play a role in the pathogenesis of JHS. This article presents an exploration of the causative factors contributing to musculoskeletal pain in individuals with hypermobility, based on research findings. It aims to provide an understanding of JHS and its association with membrane proteins, addressing the clinical manifestations, pathogenesis, diagnosis, and management of JHS.
Asunto(s)
Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Proteínas de la Membrana , Humanos , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/genética , Inestabilidad de la Articulación/metabolismo , Inestabilidad de la Articulación/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismoRESUMEN
Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.
Asunto(s)
Enfermedades del Tejido Conjuntivo , Humanos , Artritis , Colágeno/genética , Enfermedades del Tejido Conjuntivo/genética , Enfermedades del Tejido Conjuntivo/terapia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Pérdida Auditiva Sensorineural , Inestabilidad de la Articulación/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Marfan/genética , Síndrome de Marfan/diagnóstico , Osteogénesis Imperfecta/genética , Desprendimiento de RetinaRESUMEN
Heterozygous variants in KIF22, encoding a kinesin-like protein, are responsible for spondyloepimetaphyseal dysplasia with joint laxity, leptodactilic type (lepto-SEMDJL), characterized by short stature, flat face, generalized joint laxity with multiple dislocations, and progressive scoliosis and limb deformity. By targeted gene sequencing analysis, we identified a homozygous KIF22 variant (NM_007317.3: c.146G>A, p.Arg49Gln) in 3 patients from 3 unrelated families. The clinical features appeared similar to those of patients carrying heterozygous KIF22 variant (c.443C>T or c.446G>A), although the spinal involvement appeared later and was less severe in patients with a recessive variant. Relatives harboring the c.146G>A variant at the heterozygous state were asymptomatic. The homozygous KIF22 variant c.146G>A affected a conserved residue located in the active site and potentially destabilized ATP binding. RT-PCR and western blot analyses demonstrated that both dominant and recessive KIF22 variants do not affect KIF22 mRNA and protein expression in patient fibroblasts compared to controls. As lepto-SEMDJL presents phenotypic overlap with chondrodysplasias with multiple dislocations (CMD), related to defective proteoglycan biosynthesis, we analyzed proteoglycan synthesis in patient skin fibroblasts. Compared to controls, DMMB assay showed a significant decrease of total sulfated proteoglycan content in culture medium but not in the cell layer, and immunofluorescence demonstrated a strong reduction of staining for chondroitin sulfates but not for heparan sulfates, similarly in patients with recessive or dominant KIF22 variants. These data identify a new recessive KIF22 pathogenic variant and link for the first time KIF22 pathogenic variants to altered proteoglycan biosynthesis and place the lepto-SEMDJL in the CMD spectrum.
Heterozygous variants in KIF22, encoding a kinesin-like protein, are responsible for spondyloepimetaphyseal dysplasia with joint laxity, leptodactilic type (lepto-SEMDJL), characterized by short stature, flat face, generalized joint laxity with multiple dislocations, and progressive scoliosis and limb deformity. We identified a homozygous KIF22 variant (NM_007317.3: c.146G>A, p.Arg49Gln) in 3 patients from 3 unrelated families. The clinical features appeared similar to those of patients carrying heterozygous KIF22. The homozygous KIF22 variant c.146G>A affected a conserved residue located in the active site and potentially destabilized ATP binding. As lepto-SEMDJL presents phenotypic overlap with chondrodysplasias with multiple dislocations, related to defective proteoglycan biosynthesis, we analyzed proteoglycan synthesis in patient skin fibroblasts and showed a significant decrease of total sulfated proteoglycan content in culture medium, similarly in patients with recessive or dominant KIF22 variants. These data identify a new recessive KIF22 pathogenic variant and link for the first time KIF22 pathogenic variants to altered proteoglycan biosynthesis.
Asunto(s)
Inestabilidad de la Articulación , Osteocondrodisplasias , Humanos , Inestabilidad de la Articulación/genética , Cinesinas/genética , Osteocondrodisplasias/genética , Familia , Proteínas de Unión al ADNAsunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X , Errores Innatos del Metabolismo , Fosfoglicerato Quinasa , Humanos , Fosfoglicerato Quinasa/genética , Fosfoglicerato Quinasa/deficiencia , Masculino , Inestabilidad de la Articulación/genética , Femenino , Enfermedades de la Columna Vertebral/genéticaRESUMEN
BACKGROUND: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1. CONCLUSIONS: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.
Asunto(s)
Alelos , Inestabilidad de la Articulación , Factores de Transcripción , Humanos , Femenino , Adulto Joven , Factores de Transcripción/genética , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/congénito , India , Anomalías Cutáneas/genética , Anomalías Cutáneas/diagnóstico , Aracnodactilia/genética , Aracnodactilia/diagnóstico , Enfermedades del Tejido Conjuntivo/genética , Enfermedades del Tejido Conjuntivo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Linaje , Mutación , Exones/genética , Anomalías Múltiples/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/diagnóstico , Enfermedades Cutáneas Genéticas/patologíaRESUMEN
It concerns three siblings (two 28 year old twin boys and a 25 year old woman) who presented a previous history of rupture of eyeball in one eye and very poor vision in the other. At the first ophthalmoscopic and instrumental evaluation, three patients presented with bluish sclera and keratoglobus in the intact eye. A genetic analysis with whole exome sequencing was then performed on the three siblings, identifying a biallelic variant of the PRDM5 gene that led to the diagnosis of Brittle Cornea Syndrome (BCS), a rare autosomal recessive disorder characterized by corneal thinning and blue sclera. To preserve the only intact eye from possible breakage, the three siblings were trained in using protective measures (polycarbonate goggles etc.) to carry out close monitoring of symptoms and were asked to continue with follow-up visits for ocular and systemic diseases associated with BCS. Given the poor best corrected visual acuity achievable with glasses and contact lenses, penetrating keratoplasty was performed, achieving good visual acuity maintained in the 2-year follow-up in two of the three patients. Knowledge of this pathology and its clinical manifestations is essential for early diagnosis and correct management of this rare but very debilitating pathology. To our knowledge, this is the first case series of BCS reported in an Albanian population.
Asunto(s)
Anomalías del Ojo , Inestabilidad de la Articulación , Anomalías Cutáneas , Masculino , Femenino , Humanos , Adulto , Queratoplastia Penetrante , Anomalías Cutáneas/diagnóstico , Anomalías Cutáneas/genética , Anomalías Cutáneas/cirugía , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/cirugía , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/cirugía , Córnea/patologíaRESUMEN
Ehlers-Danlos syndromes (EDS) is an umbrella term describing 14 types, of which 13 are rare and monogenic, with overlapping features of joint hypermobility, skin, and vascular fragility, and generalised connective tissue friability. Hypermobile EDS currently has no identified genetic cause. Most of the rare monogenic EDS types can have neurological features, which are often part of major or minor diagnostic criteria for each type. This review aims to highlight the neurological features and other key characteristics of these EDS types. This should improve recognition of these features, enabling more timely consideration and confirmation or exclusion through genetic testing. In practice, many healthcare professionals still refer to patients as having 'EDS'. However, the different EDS types have distinct clinical features as well as different underlying genetic causes and pathogenic mechanisms, and each requires bespoke management and surveillance. Defining the EDS type is therefore crucial, as EDS is not in itself a diagnosis.
Asunto(s)
Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Enfermedades Vasculares , Humanos , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patología , Pruebas Genéticas , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genéticaRESUMEN
We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.
Asunto(s)
Cutis Laxo , Inestabilidad de la Articulación , Enfermedades de la Columna Vertebral , Masculino , Humanos , Niño , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Cutis Laxo/genética , Mutación , Vértebras Cervicales/cirugía , Vértebras Cervicales/patologíaRESUMEN
Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22. Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the progression of SEMDJL2 throughout the life of the oldest individual reported in the literature-a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.
Asunto(s)
Luxaciones Articulares , Inestabilidad de la Articulación , Osteocondrodisplasias , Masculino , Humanos , Anciano , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/patología , Luxaciones Articulares/genética , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/genética , Proteínas de Unión al ADN/genética , Cinesinas/genéticaRESUMEN
Deleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria for COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 and COL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were validated against 209 variants, and resulted effective for classifying as pathogenic and likely pathogenic null alleles without downgrading of the PVS1 level of strength and recurrent Glycine substitutions. Adaptations of selected criteria reduced uncertainties on private Glycine substitutions, intronic variants predicted to affect the splicing, and null alleles with a downgraded PVS1 level of strength. Segregation and multigene panel sequencing data mitigated uncertainties on non-Glycine substitutions by the attribution of one or more benignity criteria. These specifications may improve the clinical utility of molecular testing in HCTD by reducing the number of variants with neutral/conflicting interpretations. Close interactions between laboratory and clinicians are crucial to estimate the a priori utility of molecular test and to improve medical reports.
Asunto(s)
Variación Genética , Inestabilidad de la Articulación , Humanos , Estados Unidos , Pruebas Genéticas/métodos , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Análisis de Secuencia de ADN/métodosRESUMEN
PURPOSE: The aim of this study was to report the detailed ophthalmic findings in a young patient with genetically confirmed arterial tortuosity syndrome (ATS) and the findings in 8 family members who were carriers. METHODS: Nine members of the same Saudi family were assessed at King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, for ATS-related ocular changes after homozygosity for the pathogenic variant of SLC2A10 gene was confirmed in 1 member. All family members underwent complete ophthalmic examination, genetic testing, and corneal tomography at presentation and at 6-month follow-up. RESULTS: All ophthalmic features were manifested in our patient with ATS including schisis-like splitting of the stromal layer with greater peripheral thinning, pannus, deep posterior stromal opacities, myopia, high astigmatism, and keratoglobus. The ocular phenotype was also expressed in some carriers ranging from mild myopia to the full spectrum of corneal abnormalities associated with ATS. CONCLUSIONS: Our study provided further insights into the phenotype in both patients with ATS and carriers. Annual ophthalmic examination is warranted in both types of patients and must undergo from early life onward to detect progressive ectasia which may necessitate corneal crosslinking.
Asunto(s)
Inestabilidad de la Articulación , Queratocono , Miopía , Humanos , Córnea/patología , Queratocono/patología , Inestabilidad de la Articulación/genéticaRESUMEN
Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders.
Asunto(s)
Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Humanos , RNA-Seq , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/metabolismo , Síndrome de Ehlers-Danlos/genética , Matriz Extracelular/metabolismo , Fibroblastos/metabolismoRESUMEN
Joint laxity is a multifactorial phenotype with a heritable component. Mutations or common polymorphisms within the α1(V) (COL5A1), α1(XI) (COL11A1) and α2(XI) (COL11A2) collagen genes have been reported or proposed to associate with joint hypermobility, range of motion and/or genu recurvatum. The aim of this study was to investigate whether polymorphisms within these collagen-encoding genes are associated with measurements of knee joint laxity and computed ligament length changes within the non-dominant leg. One hundred and six healthy participants were assessed for genu recurvatum (knee hyperextension), anterior-posterior tibial translation, external-internal tibial rotation and ligament length changes during knee rotation of their non-dominant leg. Participants were genotyped for COL5A1 rs12722 (T/C), COL11A1 rs3753841 (C/T), COL11A1 rs1676486 (T/C) and COL11A2 rs1799907 (A/T). The genotype-genotype combination of any two or more of the four COL5A1 rs12722 CC, COL11A1 rs3753841 CC, COL11A1 rs1676486 TT and COL11A2 rs1799907 AA genotypes was associated with decreased active and passive knee hyperextension. These genotype-genotype combinations, including sex (male), increased age and decreased body mass collectively, also contributed to decreased passive knee hyperextension. These findings suggest that COL5A1, COL11A1 and COL11A2 gene-gene interactions are associated with knee hyperextension measurements of the non-dominant leg of healthy individuals.
Asunto(s)
Colágeno , Inestabilidad de la Articulación , Articulación de la Rodilla , Humanos , Masculino , Colágeno/genética , Genotipo , Inestabilidad de la Articulación/genética , Articulación de la Rodilla/fisiopatología , Polimorfismo GenéticoRESUMEN
BACKGROUND: Joint laxity is a multifactorial phenotype with a heritable component. Type I collagen gene (COL1A1) mutations cause connective tissue disorders with joint hypermobility as a clinical feature, while variants within COL1A1 and type III collagen gene (COL3A1) are associated with musculoskeletal injuries. The aim of this study was to investigate whether COL1A1 and COL3A1 variants are associated with measurements of non-dominant knee joint laxity and computed ligament length changes. METHODS: 106 moderately active uninjured participants were assessed for genu recurvatum, anterior-posterior tibial translation, external-internal tibial rotation and calculated ligament length changes during knee rotation. Participants were genotyped for COL1A1 rs1107946, rs1800012 and COL3A1 rs1800255. FINDINGS: The COL1A1 rs1107946 GG genotype had significantly larger external rotation [GG: 5.7° (4.9°;6.4°) vs GT: 4.6° (4.2°;5.5°), adjusted P = 0.014], internal rotation [GG: 5.9° (5.3°;6.6°) vs GT: 5.4° (4.7°;6.2°), adjusted P = 0.014], and slack [GG: 18.2° ± 3.2° vs GT: 16.1° ± 3.1°, adjusted P = 0.014]. The GG genotype at both COL1A1 variants had significantly larger active displacement [GG + GG: 6.0 mm (3.8 mm;8.0 mm) vs other genotype combinations: 4.0 mm (2.5 mm;6.0 mm), P < 0.001] and maximum displacement [GG + GG: 8.0 mm (6.9 mm;10.6 mm) vs other genotype combinations: 6.0 mm (5.0 mm;9.0 mm), P = 0.003]. COL1A1 rs1107946 significantly contributed to increased external and internal rotation in multilinear regression models, while both COL1A1 variants, significantly contributed to increased active displacement and slack. Larger medial and lateral cruciate ligament length changes were reported in participants with GG genotypes at both COL1A1 variants. INTERPRETATION: These findings suggest that the COL1A1 variants are associated with knee rotational laxity and changes in ligament length.
Asunto(s)
Cadena alfa 1 del Colágeno Tipo I , Colágeno Tipo III , Inestabilidad de la Articulación , Ligamentos Articulares , Humanos , Colágeno Tipo III/genética , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/patología , Cadena alfa 1 del Colágeno Tipo I/genética , Ligamentos Articulares/patología , Variación GenéticaRESUMEN
Ehlers-Danlos syndrome, hypermobility type (hEDS) is a heritable connective tissue disorder that currently does not have a known molecular etiology. Previous studies have explored the complex symptomology, clinical diagnosis, and psychological aspects of hEDS. Genetics providers currently aid in the diagnosis and management guidance of patients with hEDS, but there is limited data describing the needs and expectations of individuals with hEDS from a clinical genetics appointment. Our study sought to explore these items through the use of an online survey to assess participants' beliefs, needs and expectations (BNE) for genetic counseling as well as questions about demographics, hEDS symptoms, and current medical care. A total of 460 respondents with hEDS completed the survey. Most participants felt joint pain/weakness (n = 392; 88%) was one of the most disruptive symptoms of hEDS and 63% (n = 289) reported having psychiatric conditions. BNE scores were highest in two domains: expectations to have psychosocial concerns addressed during a genetic counseling appointment (mean score = 4.4/5; SD = 0.56) and desire for positive feelings after a genetic counseling session (mean score = 4.3/5; SD = 0.59). Participants who previously had genetic counseling felt less unsure about their diagnosis (p = 0.02) and had lower need for information about hEDS (p < 0.001). Majority of participants did not feel that their doctors were knowledgeable about hEDS (n = 269; 58%) and strongly supported a multidisciplinary approach to their care (n = 445; 97%). This research provides a framework for genetics providers and other healthcare professionals to assess the needs and expectations of patients with hEDS and consider re-structuring their appointment formats to service this population.