WDR45 Gene and Its Role in Pediatric Epilepsies

2021 ◽  
Author(s):  
Federica Filosco ◽  
Sebastiano Billone ◽  
Ausilia Collotta ◽  
Tiziana Timpanaro ◽  
Monica Tosto ◽  
...  
Keyword(s):  
Language Impairment ◽  
Pediatric Patients ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Brain Magnetic Resonance Imaging ◽  
Iron Accumulation ◽  
Psychomotor Development ◽  
Specific Gene ◽  
Brain Iron ◽  
De Novo Mutations

AbstractWD repeat domain 45 (WDR45) gene has been increasingly found in patients with developmental delay (DD) and epilepsy. Previously, WDR45 de novo mutations were reported in sporadic adult and pediatric patients presenting iron accumulation, while heterozygous mutations were associated with β-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation disorders, characterized by extrapyramidal movement disorders and abnormal accumulation of iron in the basal ganglia. Overall, people harboring WDR45 mutations have moderate to severe DD and different types of seizures. The phenotype of adult patients is characterized by extrapyramidal movement, dystonia, parkinsonism, language impairment, and involvement of the substantia nigra and in the globus pallidus at brain magnetic resonance imaging. Importantly, there are no findings of brain iron accumulation in brain in BPAN patients in the first decade of life, thus suggesting a progressive course of the disease. Comparatively, the main phenotype of pediatric patients is epilepsy with early onset, most of which present infantile spasms and arrest or regression of psychomotor development. The phenotype of patients with WDR45 mutations is variable, being different if caused by somatic mosaicism or germline mutations, and presenting with a different spectrum of manifestations in males and females. The treatment of affected individuals is symptomatic. Regarding the seizures, specific, gene-based approaches with specific antiepileptic drugs are not currently available. The early diagnosis of BPAN could be useful in some aspects, such as providing families a supportive treatment to their affected children.

scholarly journals A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Ana Isabel Sánchez ◽  
Jorge Armando Rojas
Keyword(s):  
Latin America ◽  
Case Report ◽  
Language Impairment ◽  
De Novo ◽  
Signs And Symptoms ◽  
Facial Features ◽  
Missense Mutations ◽  
De Novo Mutations ◽  
Lower Lip ◽  
First Case

Nicolaides-Baraitser syndrome (NCBRS) is a rare and well-recognized entity that was first described in 1993, with a prevalence that is currently not known. It is recognized as a distinctive entity, with some variability in its signs and symptoms. The most important characteristics include intellectual disability, peculiar facial features including sparse scalp hair, coarse facial features, low frontal hairline, and microcephaly, and seizures. Additional features may include epicanthic folds, thin upper lip vermilion with thick lower lip vermilion, skeletal abnormalities, and severe language impairment. The disorder is inherited in an autosomal dominant manner caused by de novo mutations in the SMARCA2 gene, with most being missense mutations. We report a young adult patient with NCBRS and, to our knowledge, the first case report of the syndrome in Latin America with a confirmed molecular diagnosis and a mild-to-moderate phenotype.

scholarly journals Novel de novo heterozygous mutation on SYNGAP1 from the Indian population

2020 ◽  
Author(s):  
Vijaya Verma ◽  
Amit Mandora ◽  
Abhijeet Botre ◽  
James Premdoss Clement
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Novel Mutation ◽  
Autism Spectrum ◽  
Current Treatment ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
Heterozygous Mutation ◽  
Specific Gene ◽  
De Novo Mutations

Abstract Background : Exome sequencing is a prominent tool to identify novel and deleterious mutations which could be nonsense, frameshift, and canonical splice-site mutations in a specific gene. De novo mutations in SYNGAP1 , which codes for synaptic RAS-GTPase activating the protein, causes Intellectual disability (ID) and Autism Spectrum Disorder (ASD). SYNGAP1 related ASD/ID is one of the rare diseases that is detrimental to the normal neuronal developmental and disrupts the global development of a child. Results: We report a case of a child of 2-year old with global developmental delay, microcephaly subtle dysmorphism, absence seizures, disrupted sleep, delay in learning a language, and eating problems. Upon further validation, the child has a few traits of ASD. Here, based on focused exome sequencing, we report a de novo heterozygous mutation in SYNGAP1 exon 11 with c. 1861 C>T (p.arg612ter). Currently, the child is on atorvastatin and has shown considerable improvement in global behaviour and cognitive development. The long-term follow up of the child’s development would contribute to the already existing knowledge of the developmental trajectory in individuals with SYNGAP1 heterozygous mutation. Conclusion: In this report, we discuss the finding of a novel mutation in one of the genes, SYNGAP1 , implicated in ASD/ID. In addition, we discuss the current treatment prescribed to the patient and the progress of global developmental of the child.

Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India

2021 ◽  
Author(s):  
Naveen Kumar Bhardwaj ◽  
Vykuntaraju K. Gowda ◽  
Jitendra Saini ◽  
Ashwin Vivek Sardesai ◽  
Rashmi Santhoshkumar ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Southern India ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Genetic Features

scholarly journals Advantages of high throughput parallel sequencing in detecting somatic mosaicism in sporadic retinoblastoma

2020 ◽  
pp. 6-7
Author(s):  
Е.А. Алексеева ◽  
О.В. Бабенко ◽  
В.М. Козлова ◽  
Т.Л. Ушакова ◽  
Т.П. Казубская ◽  
...  
Keyword(s):  
Family History ◽  
High Throughput ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Allelic Frequency ◽  
De Novo Mutations ◽  
Rb1 Gene ◽  
Parallel Sequencing ◽  
Pathogenic Variants

Почти 80% случаев наследственной ретинобластомы не имеют семейного анамнеза и возникают в результате мутаций de novo в гене RB1. Методом высокопроизводительного параллельного секвенирования (ВПС) проведено молекулярно-генетическое обследование 208 неродственных больных со спорадической РБ, среди которых 145 пациентов с унилатеральной формой заболевания и 63 - с билатеральной. В группе пациентов с билатеральной РБ молекулярные изменения в гене RB1 обнаружены в 90,5% (57/63) случаев. У 4,8% (3/63) пациентов определен мозаичный вариант мутации в гене RB1. В группе пациентов с унилатеральной РБ молекулярные изменения в гене RB1 выявлены в 17,9% (26/145) случаев. Среди исследованных пациентов соматический мозаицизм выявлен в 9,0% (13/165) случаев. Применение ВПС позволяет точно определять аллельную частоту вариантов, что делает поиск соматического мозаицизма эффективным. Almost 80% of cases of hereditary retinoblastoma do not have a family history and arise as a result of de novo mutations in the RB1 gene. An NGS test was performed on 208 unrelated patients with sporadic RB, including 145 patients with a unilateral form and 63 patients with a bilateral one. In the group of patients with bilateral RB, pathogenic variants in the RB1 gene were detected in 90.5% (57/63) cases. In 4.8% (3/63) of patients, a mosaic variants were determined. In the group of patients with unilateral RB, changes in the RB1 gene were detected in 17.9% (26/145) cases. Among the examined patients, somatic mosaicism was detected in 9.0% (13/165) cases. NGS allows us to determine the allelic frequency of variants, which makes the search for somatic mosaicism effective.

scholarly journals NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment

2018 ◽  
Vol 25 (3) ◽  
pp. 404-432 ◽  
Author(s):  
Ana Fernandez-Marmiesse ◽  
Sofia Gouveia ◽  
Maria L. Couce
Keyword(s):  
Rare Disease ◽  
Rare Diseases ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Genetic Diagnosis ◽  
De Novo Mutations ◽  
Coding Regions ◽  
Digenic Inheritance ◽  
Disease Associated Genes ◽  
Next Generation Sequencing Ngs

Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Australian population have a rare disease. Rare diseases are thus a common problem for clinicians and account for enormous healthcare costs worldwide due to the difficulty of establishing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedented, simple way of discovering novel disease-associated genes. We focus particularly on metabolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide phenotypic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the second part of the review, we look at the limitations and challenges of NGS, including determination of variant causality, the loss of variants in coding and non-coding regions, and the detection of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future.

scholarly journals Genetic Mosaicism as a Cause of Inborn Errors of Immunity

2021 ◽  
Author(s):  
Jahnavi Aluri ◽  
Megan A. Cooper
Keyword(s):  
Immune Response ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Genetic Diagnosis ◽  
Low Frequency ◽  
De Novo Mutations ◽  
Inborn Errors ◽  
Tissue Samples ◽  
Inborn Errors Of Immunity ◽  
Genetic Mosaicism

AbstractInborn errors of immunity (IEIs) are a heterogeneous group of disorders due to genetic defects in the immune response that have a broad clinical spectrum. Diagnosis of the precise genetic cause of IEI has led to improved care and treatment of patients; however, genetic diagnosis using standard approaches is only successful in ~40% of patients and is particularly challenging in “sporadic” cases without a family history. Standard genetic testing for IEI evaluates for germline changes in genes encoding proteins important for the immune response. It is now clear that IEI can also arise from de novo mutations leading to genetic variants present in germ cells and/or somatic cells. In particular, somatic mosaicism, i.e., post-zygotic genetic changes in DNA sequence, is emerging as a significant contributor to IEI. Testing for somatic mosaicism can be challenging, and both older sequencing techniques such as Sanger sequencing and newer next-generation sequencing may not be sensitive enough to detect variants depending on the platform and analysis tools used. Investigation of multiple tissue samples and specifically targeting sequence technologies to detect low frequency variants is important for detection of variants. This review examines the role and functional consequences of genetic mosaicism in IEI. We emphasize the need to refine the current exome and genome analysis pipeline to efficiently identify mosaic variants and recommend considering somatic mosaicism in disease discovery and in the first-tier of genetic analysis.

scholarly journals A rare case of a male child with post-zygotic de novo mosaic variant c.538C > T in MECP2 gene: a case report of Rett syndrome

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jhanvi Shah ◽  
Harsh Patel ◽  
Deepika Jain ◽  
Frenny Sheth ◽  
Harsh Sheth
Keyword(s):  
Rett Syndrome ◽  
Language Impairment ◽  
Rare Case ◽  
De Novo ◽  
Present Report ◽  
Case Reports ◽  
Somatic Mosaicism ◽  
Receptive Language ◽  
Dominant Mode ◽  
Severe Intellectual Disability

Abstract Background Rett syndrome (RTT) is characterized by a normal perinatal period with a normal head size at birth followed by normal development for the first 6 months of life followed by gradual deceleration of head growth, loss of acquired purposeful hand skills, severe expressive and receptive language impairment, severe intellectual disability and gait and truncal apraxia/ ataxia. It is caused due to mutations in the MECP2 gene and follows an X-linked dominant mode of inheritance. It was observed exclusively in females and was believed to be lethal in males. In contrast to this belief, several males were identified with RTT upon genetic analysis, however, most males expired by the age of 2 years due to neonatal encephalopathy. The ones that survived beyond the age of 2 years, were attributed to the presence of an extra X chromosome (co-occurrence of Klinefelter and RTT) or the ones having mosaic cell lines. Only 11 males with somatic mosaicism are known till date. Case presentation This case reports an ultra-rare case of a male affected with RTT surviving beyond the age of 2 years due to post-zygotic de novo somatic mosaicism. He was identified with a known pathogenic variant c.538C > T (p.R180*), which to the best of our knowledge is exclusively seen in females and has never been reported in a male before. Conclusion The present case is the first report of a mosaic male affected with RTT from India. The present report also carried out genotype-phenotype correlations across surviving mosaic males with RTT. We also postulate the effect of variant type, position along the gene and the variant allele fraction in different tissue types to be correlated with disease severity.

scholarly journals De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment

2010 ◽  
Vol 87 (5) ◽  
pp. 671-678 ◽  
Author(s):  
Fadi F. Hamdan ◽  
Hussein Daoud ◽  
Daniel Rochefort ◽  
Amélie Piton ◽  
Julie Gauthier ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Language Impairment ◽  
De Novo ◽  
De Novo Mutations

scholarly journals A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 344 ◽  
Author(s):  
Emanuela Leonardi ◽  
Mariagrazia Bellini ◽  
Maria C. Aspromonte ◽  
Roberta Polli ◽  
Anna Mercante ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Status Epilepticus ◽  
Behavioral Problems ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Somatic Mosaicism ◽  
Coiled Coil ◽  
Loss Of Function ◽  
De Novo Mutations

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

scholarly journals Dissecting single-cell genomes through the clonal organoid technique

2021 ◽  
Author(s):  
Jeonghwan Youk ◽  
Hyun Woo Kwon ◽  
Ryul Kim ◽  
Young Seok Ju
Keyword(s):  
Single Cell ◽  
Genome Sequencing ◽  
De Novo ◽  
Single Cells ◽  
Somatic Mosaicism ◽  
Adult Stem Cell ◽  
Clonal Expansion ◽  
De Novo Mutations ◽  
Organoid Culture

AbstractThe revolution in genome sequencing technologies has enabled the comprehensive detection of genomic variations in human cells, including inherited germline polymorphisms, de novo mutations, and postzygotic mutations. When these technologies are combined with techniques for isolating and expanding single-cell DNA, the landscape of somatic mosaicism in an individual body can be systematically revealed at a single-cell resolution. Here, we summarize three strategies (whole-genome amplification, microdissection of clonal patches in the tissue, and in vitro clonal expansion of single cells) that are currently applied for single-cell mutational analyses. Among these approaches, in vitro clonal expansion, particularly via adult stem cell-derived organoid culture technologies, yields the most sensitive and precise catalog of somatic mutations in single cells. Moreover, because it produces living mutant cells, downstream validation experiments and multiomics profiling are possible. Through the synergistic combination of organoid culture and genome sequencing, researchers can track genome changes at a single-cell resolution, which will lead to new discoveries that were previously impossible.

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