Novel Variants and Clinical Characteristics of 16 Patients from Southeast Asia with Genetic Variants in Neurofibromin-1

AbstractNeurofibromatosis type 1 (NF1) is one of the most common inherited disorders. It is caused by mutations in the neurofibromin-1 gene (NF1) and affects the formation and growth of nerve tissues. More than 3,600 pathogenic variants in the NF1 gene have been identified from patients with most of the germline variants are from the Western populations. We found 16 patients (15 Chinese and 1 Asian Indian) who had heterozygous variants in NF1 through targeted next-generation sequencing. There were 15 different variants: 4 frameshift, 4 nonsense, 5 missense, and 2 splice variants. One nonsense variant and three frameshift variants had never been reported in any population or patient database. Twelve of the 16 patients met the NF1 diagnostic criteria, and each was found to have a pathogenic or likely pathogenic variant. Three different missense variants of unknown significance were discovered in the other four patients who did not meet NF1 diagnostic criteria. Our findings add four novel variants to the list of genetic mutations linked to NF1's various clinical manifestations.

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Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

BMC Pediatrics ◽

10.1186/s12887-021-02791-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Eva Pinti ◽

Krisztina Nemeth ◽

Krisztina Staub ◽

Anna Lengyel ◽

Gyorgy Fekete ◽

...

Keyword(s):

Diagnostic Criteria ◽

Neurofibromatosis Type ◽

Early Years ◽

Diagnostic Efficiency ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Clinical Diagnostic ◽

Long Time ◽

Diagnostic Difficulties ◽

Clinical Diagnostic Criteria

Abstract Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

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Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing

Molecular Syndromology ◽

10.1159/000518927 ◽

2021 ◽

pp. 1-9

Author(s):

Pelin Ercoskun ◽

Cigdem Yuce Kahraman ◽

Guller Ozkan ◽

Abdulgani Tatar

Keyword(s):

Hereditary Cancer ◽

Hereditary Cancer Syndrome ◽

Cancer Syndrome ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

Novel Variants ◽

Genetics And Genomics ◽

Cancer Syndromes ◽

Generation Sequencing

A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the MUTYH, BRCA2, and CHEK2 genes. Nine novel pathogenic/likely pathogenic variants were identified in BRCA1, BRCA2, GALNT12, ATM, MLH1, MSH2, APC, and KIT genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.

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Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

10.21203/rs.3.rs-915593/v1 ◽

2021 ◽

Author(s):

Amein Kadhem AlAli ◽

Abdulrahman Al-Enazi ◽

Ahmed Ammar ◽

Mahmoud Hajj ◽

Cyril Cyrus ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

High Rate ◽

Variants Of Unknown Significance ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variants ◽

Unknown Significance ◽

Rare Genetic Variants

Abstract Background Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian Epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity amongst large tribal pedigrees. Results We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known Epilepsy related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline based variant prioritization approach in an attempt to discover putative causative variants. We identified a 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi Epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity were observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. Conclusion Several putative pathogenic variants known to be epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci have been identified which may be prioritized for further investigation.

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Kabuki syndrome: novel pathogenic variants, new phenotypes and review of literature

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1219-x ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 4

Author(s):

Huakun Shangguan ◽

Chang Su ◽

Qian Ouyang ◽

Bingyan Cao ◽

Jian Wang ◽

...

Keyword(s):

Clinical Manifestations ◽

Facial Dysmorphism ◽

Kabuki Syndrome ◽

Brain Abnormalities ◽

Genetic Sequencing ◽

Pathogenic Variants ◽

Dandy Walker Malformation ◽

Whole Exome ◽

Novel Variants ◽

Walker Malformation

Abstract Objective This study describes 5 novel variants of 7 KMT2D/KDM6A gene and summarizes the clinical manifestations and the mutational spectrum of 47 Chinese Kabuki syndrome (KS) patients. Methods Blood samples were collected for whole-exome sequencing (WES) for 7 patients and their parents if available. Phenotypic and genotypic spectra of 40 previously published unrelated Chinese KS patients were summarized. Result Genetic sequencing identified six KMT2D variants (c.3926delC, c.5845delC, c.6595delT, c.12630delG, c.16294C > T, and c.16442delG) and one KDM6A variant (c.2668-2671del). Of them, 4 variants (c.3926delC, c.5845delC, c.12630delG, and c.16442delG) in KMT2D gene and the variant (c.2668-2671del) in KDM6A gene were novel. Combining with previously published Chinese KS cases, the patients presented with five cardinal manifestations including facial dysmorphism, intellectual disability, growth retardation, fingertip pads and skeletal abnormalities. In addition, 29.5% (5/17) patients had brain abnormalities, such as hydrocephalus, cerebellar vermis dysplasia, thin pituitary and white matter myelination delay, corpus callosum hypoplasia and Dandy-Walker malformation. Conclusion In this report, five novel variants in KMT2D/KDM6A genes are described. A subset of Chinese KS patients presented with brain abnormalities that were not previously reported. Our study expands the mutational and phenotypic spectra of KS.

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Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

Human Genetics ◽

10.1007/s00439-021-02410-z ◽

2021 ◽

Author(s):

Hildegard Kehrer-Sawatzki ◽

David N. Cooper

Keyword(s):

Young Children ◽

Diagnostic Criteria ◽

Neurofibromatosis Type 1 ◽

Early Adulthood ◽

Neurofibromatosis Type ◽

Clinical Feature ◽

Pathogenic Variants ◽

Legius Syndrome ◽

Nf1 Gene

AbstractNeurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

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L-Type Calcium Channel: Predicting Pathogenic/Likely Pathogenic Status for Variants of Uncertain Clinical Significance

Membranes ◽

10.3390/membranes11080599 ◽

2021 ◽

Vol 11 (8) ◽

pp. 599

Author(s):

Svetlana I. Tarnovskaya ◽

Anna A. Kostareva ◽

Boris S. Zhorov

Keyword(s):

Calcium Channels ◽

Clinical Significance ◽

Heart Defects ◽

Clinical Manifestations ◽

Specific Protein ◽

Bioinformatics Tool ◽

Missense Variants ◽

Conduction Disorders ◽

Pathogenic Variants ◽

Novel Variants

(1) Background: Defects in gene CACNA1C, which encodes the pore-forming subunit of the human Cav1.2 channel (hCav1.2), are associated with cardiac disorders such as atrial fibrillation, long QT syndrome, conduction disorders, cardiomyopathies, and congenital heart defects. Clinical manifestations are known only for 12% of CACNA1C missense variants, which are listed in public databases. Bioinformatics approaches can be used to predict the pathogenic/likely pathogenic status for variants of uncertain clinical significance. Choosing a bioinformatics tool and pathogenicity threshold that are optimal for specific protein families increases the reliability of such predictions. (2) Methods and Results: We used databases ClinVar, Humsavar, gnomAD, and Ensembl to compose a dataset of pathogenic/likely pathogenic and benign variants of hCav1.2 and its 20 paralogues: voltage-gated sodium and calcium channels. We further tested the performance of sixteen in silico tools in predicting pathogenic variants. ClinPred demonstrated the best performance, followed by REVEL and MCap. In the subset of 309 uncharacterized variants of hCav1.2, ClinPred predicted the pathogenicity for 188 variants. Among these, 36 variants were also categorized as pathogenic/likely pathogenic in at least one paralogue of hCav1.2. (3) Conclusions: The bioinformatics tool ClinPred and the paralogue annotation method consensually predicted the pathogenic/likely pathogenic status for 36 uncharacterized variants of hCav1.2. An analogous approach can be used to classify missense variants of other calcium channels and novel variants of hCav1.2.

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Multifactorial and hereditary connective tissue disorders in children. diagnostic algorithms. management tactics. russian guidelines

Pediatrician (St Petersburg) ◽

10.17816/ped725-39 ◽

2016 ◽

Vol 7 (2) ◽

pp. 5-39 ◽

Cited By ~ 6

Author(s):

Larisa N Abbakumova ◽

Vadim G Arsentev ◽

Sergey F Gnusaev ◽

Irina I Ivanova ◽

Tamara I Kadurina ◽

...

Keyword(s):

Connective Tissue ◽

Diagnostic Criteria ◽

Molecular Genetic ◽

Genetic Research ◽

Clinical Manifestations ◽

Underlying Disease ◽

Additional Treatment ◽

Molecular Techniques ◽

Comprehensive Treatment ◽

Inherited Disorders

Monogenic forms of inherited disorders of connective tissue and multifactorial connective tissue dysplasia are quite common in the population. Despite the high level of modern molecular techniques, clarification of their nosology of today, still remains a distant prospect. These difficulties are due to a large variety of mutations expressed their phenotypic polymorphism clinical manifestations, the considerable size of the genes encoding the proteins of the connective tissue, a rarity major mutations and low availability of molecular genetic research methods to verify the diagnosis. Clarification of the incidence of connective tissue displasia hindered by the lack of common terminology, standardized diagnostic criteria, as well as the practical inaccessibility of modern molecular genetic techniques to identify this heterogeneous pathology. The first part is devoted to the recommendations of the pediatric aspects of diagnosis of hereditary disorders of connective tissue with agreed international diagnostic criteria, and connective tissue displasia. Details covered principles of tactics and treatment of patients with this pathology. The attention of researchers aimed at studying the problems of the modifying effect of this disease on the nature of the flow of almost all diseases. This proves the feasibility of making additions to the standards of inspection and management of these patients with the mandatory inclusion of a comprehensive treatment of the underlying disease additional treatment and rehabilitation, correcting disorders caused by comorbidities.

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2020/6137083 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Tian-Yi Cui ◽

Xue Gao ◽

Sha-Sha Huang ◽

Yan-Yan Sun ◽

Si-Qi Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Autosomal Dominant ◽

Asian Population ◽

Nonsyndromic Hearing Loss ◽

Hereditary Hearing Loss ◽

Variant Of Uncertain Significance ◽

Targeted Next Generation Sequencing ◽

Pathogenic Variants ◽

Novel Variants ◽

Uncertain Significance

Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

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Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders

Blood Advances ◽

10.1182/bloodadvances.2020001605 ◽

2020 ◽

Vol 4 (12) ◽

pp. 2578-2594

Author(s):

Vanessa Gadoury-Levesque ◽

Lei Dong ◽

Rui Su ◽

Jianjun Chen ◽

Kejian Zhang ◽

...

Keyword(s):

Genetic Variants ◽

Clinical Phenotype ◽

Genetic Diagnosis ◽

Targeted Next Generation Sequencing ◽

Disease Phenotypes ◽

Pathogenic Variants ◽

Novel Variants ◽

Prf1 Gene ◽

Generation Sequencing ◽

Careful Thought

Abstract This article explores the distribution and mutation spectrum of potential disease-causing genetic variants in hemophagocytic lymphohistiocytosis (HLH)–associated genes observed in a large tertiary clinical referral laboratory. Samples from 1892 patients submitted for HLH genetic analysis were studied between September 2013 and June 2018 using a targeted next-generation sequencing panel approach. Patients ranged in age from 1 day to 78 years. Analysis included 15 genes associated with HLH. A potentially causal genetic finding was observed in 227 (12.0%) samples in this cohort. A total of 197 patients (10.4%) had a definite genetic diagnosis. Patients with pathogenic variants in familial HLH genes tended to be diagnosed significantly younger compared with other genes. Pathogenic or likely pathogenic variants in the PRF1 gene were the most frequent. However, mutations in genes associated with degranulation defects (STXBP2, UNC13D, RAB27A, LYST, and STX11) were more common than previously appreciated and collectively represented >50% of cases. X-linked conditions (XIAP, SH2D1A, and MAGT1) accounted for 17.8% of the 197 cases. Pathogenic variants in the SLC7A7 gene were the least encountered. These results describe the largest cohort of genetic variation associated with suspected HLH in North America. Merely 10.4% of patients were identified with a clearly genetic cause by this diagnostic approach; other possible etiologies of HLH should be investigated. These results suggest that careful thought should be given regarding whether patients have a clinical phenotype most consistent with HLH vs other clinical and disease phenotypes. The gene panel identified known pathogenic and novel variants in 10 HLH-associated genes.

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CASE OF NEUROFIBROMATOSIS TYPE I WITH ASTROCYTOMA OF THE BRAIN IN THE PRACTICE OF PEDIATRICIAN

Journal of Volgograd State Medical University ◽

10.19163/1994-9480-2020-3(75)-138-144 ◽

2020 ◽

Vol 75 (3) ◽

pp. 138-144

Author(s):

T.N. Buchkova ◽

◽

N.I. Zriachkin ◽

G.I. Chebotareva ◽

O.V. Tihnenko ◽

...

Keyword(s):

Diagnostic Criteria ◽

Clinical Case ◽

Clinical Manifestations ◽

Neurofibromatosis Type ◽

Speech Disorders ◽

Endocrine Disorders ◽

Type I ◽

Neurofibromatosis Type I ◽

Cutaneous Manifestations ◽

The Brain

The relevance of the topic is due to insufficient awareness of doctors about neurofibromatosis, which leads to a delay in diagnosis and the development of complications. The diagnostic criteria characteristic of this disease, features of the clinical course, possible complications, methods of treatment, features of dispensary observation are described. A clinical case of neurofibromatosis type I with astrocytoma of the brain is described. The diagnosis of neurofibromatosis type I (NFI) was established in a patient aged 4 years 3 months. The peculiarity of the manifestations of this clinical case is the absence of family history; the combination of cutaneous manifestations, multiple lesions of the nervous system, complicated by chronic subdural hematoma, endocrine disorders and extra-cutaneous manifestations (eye symptoms, hearing and speech disorders); the absence of significant positive dynamics despite repeated surgical treatment and long-term polyochemotherapy. Despite the stabilization of clinical manifestations of the disease, this patient has an unfavorable prognosis with possible progression of the pathological process. For early clinical detection of patients with NFI, using for this purpose diagnostic criteria recommended by the International Committee of experts on neurofibromatosis, continuity of management and adequate measures of primary and secondary prevention of complications of NFI is important knowledge of this pathology by primary health care physicians, including pediatricians, district and family doctors, neurologists, dermatologists, ophthalmologists and surgeons.

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