scholarly journals Prenatal Genetic Diagnosis in Three Fetuses With Left Heart Hypoplasia (LHH) From Three Unrelated Families

2021 ◽  
Vol 8 ◽  
Author(s):  
Sukun Luo ◽  
Luyi Chen ◽  
Weizhong Wei ◽  
Li Tan ◽  
Meng Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Heart Defects ◽  
Genetic Diagnosis ◽  
Severe Form ◽  
Left Heart ◽  
Whole Exome ◽  
Number Variation ◽  
Cardiovascular Defects ◽  
First Time ◽  
Generation Sequencing

Background: Congenital heart defects (CHDs) are the most common birth defects, and left heart hypoplasia (LHH) is a severe form of CHD and responsible for more than 20% cardiac deaths during the first week of life, however, its genetic causes remain largely elusive.Methods: Three families with fetal LHH were recruited. Genomic DNA from amniotic fluid or peripheral blood, and trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were performed.Results: All the three couples had no family history, and mid-gestation ultrasound revealed LHH and other variable cardiovascular defects in the fetuses. Trio-WES revealed de novo pathogenic variations in KMT2D (p.Gly3465Aspfs*37) (NM_003482) and WDFY3 (p.Ser117Xfs*) (NM_014991), and CNV-seq identified a deletion of 150 kb encompassing NOTCH1. KMT2D and NOTCH1 previously have been reported to be associated with CHDs, however, WDFY3 is reported for the first time to be possibly related to CHD in human.Conclusion: Our study suggested that genetic component is an important risk factor for the development of LHH, and next generation sequencing is a powerful tool for genetic diagnosis in fetuses with CHDs and genetic counseling, however, more studies and data are need to establish the correlation of fetal phenotypes and genotypes.

scholarly journals New Genotypes and Phenotypes in Patients with 3 Subtypes of Waardenburg Syndrome Identified by Diagnostic Next-Generation Sequencing

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Wu Li ◽  
Lingyun Mei ◽  
Hongsheng Chen ◽  
Xinzhang Cai ◽  
Yalan Liu ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
De Novo ◽  
Waardenburg Syndrome ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Number Variation ◽  
First Time ◽  
Generation Sequencing

Background. Waardenburg syndrome (WS) is one of the most common forms of syndromic deafness with heterogeneity of loci and alleles and variable expressivity of clinical features. Methods. The technology of single-nucleotide variants (SNV) and copy number variation (CNV) detection was developed to investigate the genotype spectrum of WS in a Chinese population. Results. Ninety WS patients and 24 additional family members were recruited for the study. Fourteen mutations had not been previously reported, including c.808C>G, c.117C>A, c.152T>G, c.803G>T, c.793-3T >G, and c.801delT on PAX3; c.642_650delAAG on MITF; c.122G>T and c.127C>T on SOX10; c.230C>G and c.365C>T on SNAI2; and c.481A>G, c.1018C>G, and c.1015C>T on EDNRB. Three CNVs were de novo and first reported in our study. Five EDNRB variants were associated with WS type 1 in the heterozygous state for the first time, with a detection rate of 22.2%. Freckles occur only in WS type 2. Yellow hair, amblyopia, congenital ptosis, narrow palpebral fissures, and pigmentation spots are rare and unique symptoms in WS patients from China. Conclusions. EDNRB should be considered as another prevalent pathogenic gene in WS type 1. Our study expanded the genotype and phenotype spectrum of WS, and diagnostic next-generation sequencing is promising for WS.

Identification of a novel c.3080delC JAG1 gene mutation associated with Alagille syndrome by whole-exome sequencing (Preprint)

2021 ◽  
Author(s):  
Dr. Deepak Panwar ◽  
Dr. Kumar Gautam Singh ◽  
Ms. Shruti Mathur ◽  
Mr. Bhagwati Prasad ◽  
Ms. Anita Joshi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heart Defects ◽  
Genetic Diagnosis ◽  
Alagille Syndrome ◽  
Sequencing Analysis ◽  
Next Generation ◽  
Whole Exome ◽  
Generation Sequencing

BACKGROUND Alagille syndrome is an autosomal dominant disorder associated with variable clinical phenotypic features including cholestasis, congenital heart defects, vertebral defects, and dysmorphic facies. OBJECTIVE Whole-exome sequencing (WES) has become technically feasible due to the recent advances in next-generation sequencing technologies, therefore offering new opportunities for mutations/genes identification. METHODS Next-generation sequencing (NGS) - Whole-exome sequencing was used to identify pathogenic variants of the proband. In this paper, we have uncovered a novel JAG1 mutation associated with Alagille syndrome in a 5 years old girl presented with conjugated hyperbilirubinemia and infantile cholestasis. RESULTS The exome sequencing analysis revealed the presence of a novel JAG1 heterozygous c.3080delC variant in exon 25. The detected mutation determines a stop codon (p.P1027RfsTer9) in the gene sequence, encoding a truncated protein. Our exome observations were confirmed through Sanger sequencing as well. CONCLUSIONS Here, we report a case of a patient diagnosed with Alagille syndrome, and our finding emphasis the detection of novel JAG1 mutation associated with Alagille syndrome variants thereby, establishing the genetic diagnosis of the disease. CLINICALTRIAL N/A

scholarly journals A novel 14q13.1–21.1 deletion identified by CNV-Seq in a patient with brain-lung-thyroid syndrome, tooth agenesis and immunodeficiency

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuyun Hu ◽  
Jun Liu ◽  
Ruolan Guo ◽  
Jun Guo ◽  
Zhipeng Zhao ◽  
...  
Keyword(s):  
De Novo ◽  
Deletion Syndrome ◽  
Tooth Agenesis ◽  
Diagnostic Strategy ◽  
Genomic Disorder ◽  
Case Presentation ◽  
Whole Exome ◽  
Number Variation ◽  
Phenotype Heterogeneity ◽  
Genomic Disorders

Abstract Background Chromosome 14q11-q22 deletion syndrome (OMIM 613457) is a rare genomic disorder. The phenotype heterogeneity depends on the deletion size, breakpoints and genes deleted. Critical genes like FOXG1, NKX2–1, PAX9 were identified. Case presentation We performed whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) for a patient with mild speech and motor developmental delay, short stature, recurrent pulmonary infections, tooth agenesis and triad of brain-lung-thyroid syndrome. By using CNV-seq, we identified a 3.1 Mb de novo interstitial deletion of the 14q13.2q21.1 region encompassing 17 OMIM genes including NKX2–1, PAX9 and NFKBIA. Our patient’s phenotype is consistent with other published 14q13 deletion patients. Conclusion Our results showed the combination of WES and CNV-seq is an effective diagnostic strategy for patients with genetic or genomic disorders. After reviewing published patients, we also proposed a new critical region for 14q13 deletion syndrome with is a more benign disorder compared to 14q11-q22 deletion syndrome.

scholarly journals From vascular biology to vascular medicine

2018 ◽  
Vol 2 (s1) ◽  
pp. 1-4
Author(s):  
Stefano Paolacci ◽  
Yeltay Rakhmanov ◽  
Paolo Enrico Maltese ◽  
Matteo Bertelli
Keyword(s):  
Congenital Heart Defects ◽  
Clinical Utility ◽  
Congenital Heart ◽  
Vascular System ◽  
Heart Defects ◽  
Vascular Anomalies ◽  
Clinical Validity ◽  
Vascular Medicine ◽  
Cardiovascular Defects ◽  
Generation Sequencing

Abstract Cardiovascular disorders include various conditions characterized by morphological and functional defects of the heart and vascular system. Molecular biology techniques (in particular DNA sequencing) have recently offered new insights into the etiology of cardiovascular defects, revealing their association with germline as well as somatic mutations. Genetic tests are evaluated on the basis of their analytical and clinical validity, clinical utility, and ethical, legal and social implications. Next generation sequencing is so far the best approach for molecular diagnosis of congenital heart defects and vascular anomalies, the genetic and phenotypic heterogeneity of which makes them difficult to diagnose. Understanding the molecular causes of congenital heart defects and vascular anomalies has permitted clinical trials of drugs targeting affected genes and pathways. The articles in this Special Issue aim to provide guidance for those concerned with diagnosis and research in the field of cardiovascular defects. The approach to genetic testing is discussed.

scholarly journals Case Report: Identification of a de novo Microdeletion 1q44 in a Patient With Seizures and Developmental Delay

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiehen Tung ◽  
Haiying Lu ◽  
Wenxin Lin ◽  
Tingting Huang ◽  
Samuel Kim ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Clinical Symptoms ◽  
Karyotype Analysis ◽  
Microdeletion Syndrome ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
Number Variation ◽  
History Of

Objective: 1q44 microdeletion syndrome is difficult to diagnose due to the wide phenotypic spectrum and strong genetic heterogeneity. We explore the correlation between the chromosome microdeletions and phenotype in a child with 1q44 microdeletion syndrome, we collected the clinical features of the patient and combined them with adjacent copy number variation (CNV) regions previously reported.Methods: We collected the full medical history of the patient and summarized her clinical symptoms. Whole-exome sequencing (WES) and CapCNV analysis were performed with DNA extracted from both the patient's and her parents' peripheral blood samples. Fluorescent quantitative PCR (q-PCR) was performed for the use of verification to the CNV regions.Results: A 28.7 KB microdeletion was detected in the 1q44 region by whole-exome sequencing and low-depth whole-genome sequencing. The deleted region included the genes COX20 and HNRNPU. As verification, karyotype analysis showed no abnormality, and the results of qPCR were consistent with that of whole-exome sequencing and CapCNV analysis.Conclusion: The patient was diagnosed with 1q44 microdeletion syndrome with clinical and genetic analysis. Analyzing both whole-exome sequencing and CapCNV analysis can not only improve the diagnostic rate of clinically suspected syndromes that present with intellectual disability (ID) and multiple malformations but also support further study of the correlation between CNVs and clinical phenotypes. This study lays the foundation for the further study of the pathogenesis of complex diseases.

scholarly journals DeNovoCNN: A deep learning approach to de novo variant calling in next generation sequencing data

2021 ◽  
Author(s):  
Gelana Khazeeva ◽  
Karolis Sablauskas ◽  
Bart van der Sanden ◽  
Wouter Steyaert ◽  
Michael Kwint ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Genetic Disorders ◽  
Variant Calling ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Accurate Identification ◽  
Whole Exome ◽  
De Novo Variant ◽  
Generation Sequencing

De novo mutations (DNMs) are an important cause of genetic disorders. The accurate identification of DNMs from sequencing data is therefore fundamental to rare disease research and diagnostics. Unfortunately, identifying reliable DNMs remains a major challenge due to sequence errors, uneven coverage, and mapping artifacts. Here, we developed a deep convolutional neural network (CNN) DNM caller (DeNovoCNN), that encodes alignment of sequence reads for a trio as 160×164 resolution images. DeNovoCNN was trained on DNMs of whole exome sequencing (WES) of 2003 trios achieving on average 99.2% recall and 93.8% precision. We find that DeNovoCNN has increased recall/sensitivity and precision compared to existing de novo calling approaches (GATK, DeNovoGear, Samtools) based on the Genome in a Bottle reference dataset. Sanger validations of DNMs called in both exome and genome datasets confirm that DeNovoCNN outperforms existing methods. Most importantly, we show that DeNovoCNN is robust against different exome sequencing and analyses approaches, thereby allowing it to be applied on other datasets. DeNovoCNN is freely available and can be run on existing alignment (BAM/CRAM) and variant calling (VCF) files from WES and WGS without a need for variant recalling.

Duchenne Muscular Dystrophy and Early Onset Hypertrophic Cardiomyopathy associated with Mutations in Dystrophin and Hypertrophic Cardiomyopathy-Associated Genes

2020 ◽  
Author(s):  
Liam Aspit ◽  
Noga Arwas ◽  
Aviva Levitas ◽  
Hanna Krymko ◽  
Yoram Etzion ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Hypertrophic Cardiomyopathy ◽  
Muscular Dystrophy ◽  
Early Onset ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Dystrophin Gene ◽  
Whole Exome ◽  
Rare Phenotype ◽  
Muscular Damage

AbstractDuchenne muscular dystrophy (DMD) is a progressive muscular damage disorder caused by mutations in dystrophin gene. Cardiomyopathy may first be evident after 10 years of age and increases in incidence with age. We present a boy diagnosed at 18 months with a rare phenotype of DMD in association with early-onset hypertrophic cardiomyopathy (HCM). The cause of DMD is a deletion of exons 51–54 of dystrophin gene. The cause of HCM was verified by whole exome sequencing. Novel missense variations in two genes: MAP2K5 inherited from the mother and ACTN2 inherited from the father, or de novo. The combination of MAP2K5, ACTN2, and dystrophin mutations, could be causing the HCM in our patient. This is the second patient diagnosed, at relatively young age, with DMD and HCM, with novel variations in genes known to cause HCM. This study demonstrates the need for genetic diagnosis to elucidate the underlying pathology of HCM.

scholarly journals Genetic landscape of pediatric movement disorders and management implications

2018 ◽  
Vol 4 (5) ◽  
pp. e265 ◽  
Author(s):  
Dawn Cordeiro ◽  
Garrett Bullivant ◽  
Komudi Siriwardena ◽  
Andrea Evans ◽  
Jeff Kobayashi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Movement Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Genetic Diagnosis ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Generation Sequencing

ObjectiveTo identify underlying genetic causes in patients with pediatric movement disorders by genetic investigations.MethodsAll patients with a movement disorder seen in a single Pediatric Genetic Movement Disorder Clinic were included in this retrospective cohort study. We reviewed electronic patient charts for clinical, neuroimaging, biochemical, and molecular genetic features. DNA samples were used for targeted direct sequencing, targeted next-generation sequencing, or whole exome sequencing.ResultsThere were 51 patients in the Pediatric Genetic Movement Disorder Clinic. Twenty-five patients had dystonia, 27 patients had ataxia, 7 patients had chorea-athetosis, 8 patients had tremor, and 7 patients had hyperkinetic movements. A genetic diagnosis was confirmed in 26 patients, including in 20 patients with ataxia and 6 patients with dystonia. Targeted next-generation sequencing panels confirmed a genetic diagnosis in 9 patients, and whole exome sequencing identified a genetic diagnosis in 14 patients.ConclusionsWe report a genetic diagnosis in 26 (51%) patients with pediatric movement disorders seen in a single Pediatric Genetic Movement Disorder Clinic. A genetic diagnosis provided either disease-specific treatment or effected management in 10 patients with a genetic diagnosis, highlighting the importance of early and specific diagnosis.

scholarly journals Severe Generalized Epidermolysis Bullosa Simplex in Two Hong Kong Children due to De Novo Variants in KRT14 and KRT5

2020 ◽  
Vol 2020 ◽  
pp. 1-5 ◽  
Author(s):  
Shuk Ching Chong ◽  
Kam Lun Hon ◽  
Fernando Scaglia ◽  
Chung Mo Chow ◽  
Yu Ming Fu ◽  
...  
Keyword(s):  
Hong Kong ◽  
Epidermolysis Bullosa ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Recurrence Risk ◽  
Severe Form ◽  
Epidermolysis Bullosa Simplex ◽  
First Case ◽  
Heterozygous Variant ◽  
History Of

We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.

scholarly journals Identification of novel CSNK2A1 variants and the genotype–phenotype relationship in patients with Okur–Chung neurodevelopmental syndrome: a case report and systematic literature review

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110170
Author(s):  
Ruo-hao Wu ◽  
Wen-ting Tang ◽  
Kun-yin Qiu ◽  
Xiao-juan Li ◽  
Dan-xia Tang ◽  
...  
Keyword(s):  
De Novo ◽  
Facial Dysmorphism ◽  
Comprehensive Overview ◽  
Protein Coding ◽  
Coding Regions ◽  
Gtp Binding ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
First Time ◽  
Binding Loop

De novo germline variants of the casein kinase 2α subunit (CK2α) gene ( CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur–Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype–phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1 variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype–phenotype relationship in OCNS.

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