scholarly journals DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature

2021 ◽  
Vol 11 (4) ◽  
pp. 582-593
Author(s):  
Ugo Sorrentino ◽  
Chiara Piccolo ◽  
Chiara Rigon ◽  
Valeria Brasson ◽  
Eva Trevisson ◽  
...  
Keyword(s):  
Clinical History ◽  
Auditory Hair Cells ◽  
Pathogenic Variants ◽  
Normal Expression ◽  
Large Panel ◽  
History Of ◽  
Syndromic Hearing Loss ◽  
And Function ◽  
Actin Protein ◽  
Generation Sequencing

Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the ACTG1 gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. ACTG1 gene encodes gamma actin, the predominant actin protein in the cytoskeleton of auditory hair cells; its normal expression and function are essential for the stereocilia maintenance. Different gain-of-function pathogenic variants of ACTG1 have been associated with two major phenotypes: DFNA20/26 and Baraitser–Winter syndrome, a multiple congenital anomaly disorder. Here, we report a novel ACTG1 variant [c.625G>A (p. Val209Met)] in an adult patient with moderate-severe NSHL characterized by a downsloping audiogram. The patient, who had a clinical history of slowly progressive NSHL and tinnitus, was referred to our laboratory for the analysis of a large panel of NSHL-associated genes by next generation sequencing. An extensive review of previously reported ACTG1 variants and their associated phenotypes was also performed.

A De Novo Mosaic PHEX Variant Causing Sporadic X-Linked Hypophosphatemic Rickets in a 2-Year-Old Girl

2021 ◽  
Author(s):  
Kok-Siong Poon ◽  
Karen Mei-Ling Tan ◽  
Margaret Zacharin ◽  
Cindy Wei-Li Ho
Keyword(s):  
De Novo ◽  
Sporadic Case ◽  
Hypophosphatemic Rickets ◽  
Genu Varum ◽  
Splice Donor ◽  
Mosaic Pattern ◽  
Pathogenic Variants ◽  
Phex Gene ◽  
History Of ◽  
Generation Sequencing

AbstractPathogenic variants in the PHEX gene are causative of X-linked hypophosphatemic rickets (XLH). We present a case of a 2-year-old girl with hypophosphatemic rickets with genu varum and short stature without any family history of XLH. Next generation sequencing of the PHEX gene identified a splice donor variant, NM_000444.6:c.1173 + 5G > A in intron 10. This variant had a mosaic pattern with only 22% of the sequence reads showing the variant allele and was not present in the girl's parents, both of whom had a normal phenotype. This is a sporadic case of a de novo mosaic splice-site variant in the PHEX gene.

scholarly journals Primary Side Sclerosis, Case Report and Bibliographic Review

2020 ◽  
Vol 5 (1) ◽  
Keyword(s):  
Motor Neuron ◽  
Rare Disease ◽  
Clinical History ◽  
Middle Finger ◽  
Motor Neuron Diseases ◽  
Left Limb ◽  
History Of ◽  
Low Incidence ◽  
The Right ◽  
And Function

Introduction: Primary lateral sclerosis is a rare disease that involves the upper motor neuron, producing a bulbospinal spasticity. The course of the disease is insidious and progressive, usually beginning with the lower extremities, and subsequently becoming a tetrapyramidal syndrome. Being a rare disease, the diagnosis in most cases is exclusion, having to study the patient extensively, in a clinical manner, including a thorough clinical history, laboratory and with relevant cabinet studies. Clinical Case: This is a male patient who started his clinical picture about a year ago with weakness in the left pelvic limb, later accompanied by pain and paraesthesia, manifesting the same symptoms later in the contralateral leg and upper left limb. Currently, hypoesthesia of the index and middle toes of the right foot is added, moderate tremor in the left arm, with overlapping of the middle finger over the ring of said hand. He has an inability to lift light objects for short periods of time, as well as fatigue in short periods of time when performing daily activities, which greatly limits his daily life. Conclusions: Motor neuron diseases are divided into two groups, and in the case studied, the upper motor neuron is exclusively affected. Being a rare disease, with a low incidence, multiple differential diagnoses will be considered before concluding this, considering a diagnosis of exclusion. The natural history of the disease will always have a bleak outcome, with a poor prognosis for life and function, despite the measures taken to modify its course.

scholarly journals Improving the Management of Patients with Hearing Loss by the Implementation of an NGS Panel in Clinical Practice

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1467
Author(s):  
Gema García-García ◽  
Alba Berzal-Serrano ◽  
Piedad García-Díaz ◽  
Rebeca Villanova-Aparisi ◽  
Sara Juárez-Rodríguez ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Targeted Ngs ◽  
Syndromic Hearing Loss ◽  
Genetics And Genomics ◽  
Custom Panel ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

A cohort of 128 patients from 118 families diagnosed with non-syndromic or syndromic hearing loss (HL) underwent an exhaustive clinical evaluation. Molecular analysis was performed using targeted next-generation sequencing (NGS) with a custom panel that included 59 genes associated with non-syndromic HL or syndromic HL. Variants were prioritized according to the minimum allele frequency and classified according to the American College of Medical Genetics and Genomics guidelines. Variant(s) responsible for the disease were detected in a 40% of families including autosomal recessive (AR), autosomal dominant (AD) and X-linked patterns of inheritance. We identified pathogenic or likely pathogenic variants in 26 different genes, 15 with AR inheritance pattern, 9 with AD and 2 that are X-linked. Fourteen of the found variants are novel. This study highlights the clinical utility of targeted NGS for sensorineural hearing loss. The optimal panel for HL must be designed according to the spectrum of the most represented genes in a given population and the laboratory capabilities considering the pressure on healthcare.

scholarly journals Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Wang ◽  
Jiale Xiang ◽  
Lisha Chen ◽  
Hongyu Luo ◽  
Xiuhua Xu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Multiplex Pcr ◽  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Nonsyndromic Hearing Loss ◽  
Secondary Findings ◽  
Pathogenic Variants ◽  
Molecular Etiology ◽  
Syndromic Hearing Loss ◽  
Generation Sequencing

AbstractHearing loss is one of the most common birth disorders in humans, with an estimated prevalence of 1–3 in every 1000 newborns. This study investigates the molecular etiology of a hearing loss cohort using a stepwise strategy to effectively diagnose patients and address the challenges posed by the genetic heterogeneity and variable mutation spectrum of hearing loss. In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first step; patients which did not receive a diagnosis from this were further referred for exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled in the study. In total, 64% (59/92) of the patients were molecularly diagnosed, 44 of them in the first step by multiplex PCR plus sequencing. Exome sequencing resulted in eleven diagnoses (23%, 11/48) and four probable diagnoses (8%, 4/48) among the 48 patients who were not diagnosed in the first step. The rate of secondary findings from exome sequencing in our cohort was 3% (2/58). This research presents a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrates the benefits of using a stepwise diagnostic approach in the genetic testing of nonsyndromic hearing loss.

Definition and classification of hereditary angioedema

2020 ◽  
Vol 41 (6) ◽  
pp. S03-S07 ◽  
Author(s):  
Steven P. Proper ◽  
William J. Lavery ◽  
Jonathan A. Bernstein
Keyword(s):  
Hereditary Angioedema ◽  
De Novo ◽  
Clinical History ◽  
Factor Xii ◽  
Life Threatening ◽  
History Of ◽  
Underlying Causes ◽  
Serping1 Gene ◽  
And Function

Hereditary angioedema (HAE) is defined as a rare genetic disease with recurrent episodes of localized bradykinin-mediated swelling of the deep tissues of the skin, respiratory, and gastrointestinal tracts that can be life threatening. Classification of HAE has evolved over time with our further understanding of clinical phenotypes, underlying causes, and available testing. In most cases, HAE is caused by a deficiency of C1-esterase inhibitor (C1-INH) on the Serpin Family G Member 1 (SERPING1) gene, either through decreased amounts of C1-INH protein (C1-INH‐HAE, type 1) or decreased function of C1-INH (C1-INH‐HAE, type 2). HAE with normal C1-INH levels and function are divided into unknown cause or into non‐C1-INH‐HAE forms, which include known mutational defects in factor XII (called FXII-HAE in the Hereditary Angioedema International Working Group consensus), angiopoietin-1, plasminogen, and kininogen 1 genes. It is possible that, after an initial workup, a patient without a family history of HAE could be classified with an acquired form of angioedema (nonhereditary) that may later prove to be HAE due to a de-novo SERPING1 mutation. Because there are forms of nonhistaminergic (H1-antihistamine unresponsive) angioedema that appear clinically very similar to HAE, it is essential that the patient undergoes a thorough clinical history and diagnostic evaluation to ensure that he or she is properly diagnosed and classified.

scholarly journals Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

2020 ◽  
Author(s):  
Jing Wang ◽  
Jiale Xiang ◽  
Lisha Chen ◽  
Hongyu Luo ◽  
Jingjing Xu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Multiplex Pcr ◽  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Genetic Test ◽  
Secondary Findings ◽  
Pathogenic Variants ◽  
Molecular Etiology ◽  
Syndromic Hearing Loss ◽  
Generation Sequencing

Background Hearing loss is one of the most common birth disorders in humans with an estimated prevalence of 1-3 in every 1000 newborns. This study has investigated the molecular etiology of a deaf cohort using a stepwise strategy to effectively diagnose patients and the challenges faced to verify genetic heterogenicity and the variable mutation spectrums of hearing loss. Methods In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first tier, while undiagnosed cases were further referred to exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled. Results In total, 64% (59/92) of patients were molecularly diagnosed, 44 of which were identified in the first tier by multiplex PCR plus sequencing. Of 48 undiagnosed patients from the first tier, exome sequencing identified eleven diagnoses (23%, 11/48) and four probably diagnoses (8%, 4/48). The rate of secondary findings of exome sequencing in our cohort is 3.4%. Conclusion The research presented a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrated the benefits of using the stepwise diagnostic approach in the genetic test of the non-syndromic hearing loss patient cohort.

scholarly journals Case Report: Novel Compound Heterozygous Variants in TRIOBP Associated With Congenital Deafness in a Chinese Family

2021 ◽  
Vol 12 ◽  
Author(s):  
Cong Zhou ◽  
Yuanyuan Xiao ◽  
Hanbing Xie ◽  
Jing Wang ◽  
Shanling Liu
Keyword(s):  
Autosomal Recessive ◽  
Actin Binding ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Heterozygous Carriers ◽  
Compound Heterozygous Variants ◽  
And Function ◽  
Population Databases ◽  
Generation Sequencing

Autosomal recessive non-syndromic deafness-28 (DFNB28) is characterized by prelingual, profound sensorineural hearing loss (HL). The disease is related to variants of the TRIOBP gene. TRIO and F-actin binding protein (TRIOBP) plays crucial roles in modulating the assembly of the actin cytoskeleton and are responsible for the proper structure and function of stereocilia in the inner ear. This study aimed to identify pathogenic variants in a patient with HL. Genomic DNA obtained from a 33-year-old woman with HL was evaluated using a disease-targeted gene panel. Using next generation sequencing and bioinformatics analysis, we identified two novel TRIOBP c.1170delC (p.S391Pfs*488) and c.3764C > G (p.S1255*) variants. Both parents of the patient were heterozygous carriers of the gene. The two variants have not been reported in general population databases or published literature. The findings of this study will broaden the spectrum of pathogenic variants in the TRIOBP gene.

Kedudukan dan Fungsi Bahasa dalam Permuseuman

Metahumaniora ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 54
Author(s):  
Erlina Zulkifli Mahmud ◽  
Taufik Ampera ◽  
Yuyu Yohana Risagarniwa ◽  
Inu Isnaeni Sidiq
Keyword(s):  
Human Life ◽  
Field Research ◽  
Communicative Function ◽  
Language Functions ◽  
The Past ◽  
Library Research ◽  
History Of ◽  
And Function ◽  
Museum Guides ◽  
Bahasa Indonesia

Kedudukan dan fungsi bahasa sebagai alat komunikasi manusia mencakup seluruh bidang kehidupan termasuk ilmu pengetahuan antara lain terkait sejarah peradaban manusia; bagaimana manusia mempertahankan hidupnya, bagaimana manusia memperlakukan alam, bagaimana alam menyediakan segala kebutuhan manusia. Apa yang dilakukan manusia saat ini, saat lampau, dan apa yang dilakukan manusia jauh di masa prasejarah, bagaimana kondisi alam di masa-masa tersebut, apa perubahan dan perkembangannya, dapat didokumentasikan melalui bahasa, divisualisasikan kembali, lalu dipajang sebagai salah satu upaya konversai dan preservasi dalam satu institusi yang disebut museum. Penelitian ini membahas kedudukan dan fungsi bahasa dalam permuseuman. Bagaimana kedudukan dan fungsi bahasa dalam permuseuman baik dalam informasi yang disampaikan oleh pemandu wisata museumnya maupun yang terpajang menyertai benda-benda dan gambar-gambar merupakan tujuan dari penelitian ini. Metode penelitian yang digunakan adalah gabungan antara metode lapangan dan metode literatur. Hasil penelitian menunjukkan bahwa secara umum kedudukan bahasa Indonesia berada pada urutan pertama setelah Bahasa Inggris dan keberadaan kedua bahasa dalam permuseuman ini melibatkan dua fungsi utama bahasa, yakni fungsi komunikatif dan fungsi informatif.The existence and function of language  as a medium of communication covers all fields of human life including knowledge, one of them is the history of human civilization; how humans survived, how human utilized nature for their lives, and how nature provides all the necessities for humans. What humans have been doing now, what they have done in the past and far before that in the pre-history time, how the conditions of the nature at those times were and what changes as well as progresses occurred are documented using language, then re-visualized,  displayed as one of conservation and preservation acts in an institution called museum. This research discusess the existence and function of language in museums. How important the existence of a language in museums and what language functions used in museums both in informations given by the museum guides and on the displays accompanying objects and pictures are the aims of this research. The methods used are the combination between field research and library research. The results show that generally the existence of Indonesian language plays more important role than English and both languages have two main functions; communicative function and informative function.     

Component resolved diagnostics in peanut sensitized children with and without a history of clinical reaction

2020 ◽  
Vol 41 (5) ◽  
pp. 336-340
Author(s):  
Yasmin Hamzavi Abedi ◽  
Cristina P. Sison ◽  
Punita Ponda
Keyword(s):  
Retrospective Chart Review ◽  
Clinical History ◽  
Specific Ige ◽  
Exact Test ◽  
Ara H 1 ◽  
Sige Level ◽  
History Of ◽  
Laboratory Procedures ◽  
Ige Mediated ◽  
The Relationship

Background: Serum Peanut-specific-IgE (PN-sIgE) and peanut-component-resolved-diagnostics (CRD) are often ordered simultaneously in the evaluation for peanut allergy. Results often guide the plans for peanut oral challenge. However, the clinical utility of CRD at different total PN-sIgE levels is unclear. A commonly used predefined CRD Ara h2 cutoff value in the literature predicting probability of peanut challenge outcomes is 0.35kUA/L. Objective: To examine the utility of CRD in patients with and without a history of clinical reactivity to peanut (PN). Methods: This was a retrospective chart review of 196 children with PN-sIgE and CRD testing, of which, 98 patients had a clinical history of an IgE-mediated reaction when exposed to PN and 98 did not. The Fisher's exact test was used to assess the relationship between CRD and PN-sIgE at different cutoff levels, McNemar test and Gwet’s approach (AC1 statistic) were used to examine agreement between CRD and PN-sIgE, and logistic regression was used to assess differences in the findings between patients with and without reaction history. Results: Ara h 1, 2, 3, or 9 (ARAH) levels ≤0.35 kUA/L were significantly associated with PN-sIgE levels <2 kUA/L rather than ≥2 kUA/L (p < 0.0001). When the ARAH threshold was increased to 1 kUA/L and 2 kUA/L, these thresholds were still significantly associated with PN-sIgE levels of <2, <5, and <14 kUA/L. These findings were not significantly different in patients with and without a history of clinical reactivity. Conclusion: ARAH values correlated with PN-sIgE. Regardless of clinical history, ARAH levels are unlikely to be below 0.35, 1, or 2 kUA/L if the PN-sIgE level is >2 kUA/L. Thus, if possible, practitioners should consider PN-sIgE rather than automatically ordering CRD with PN-sIgE every time. Laboratory procedures that allow automatically and reflexively adding CRD when the PN-sIgE level is ≤5 kUA/L can be helpful. However, further studies are needed in subjects with challenge-proven PN allergy.

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