scholarly journals 12q14 microduplication: a new clinical entity reciprocal to the microdeletion syndrome?

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Sofia Dória ◽  
Daniela Alves ◽  
Maria João Pinho ◽  
Joel Pinto ◽  
Miguel Leão
Keyword(s):  
Growth Regulation ◽  
De Novo ◽  
Failure To Thrive ◽  
Clinical Entity ◽  
Pcr Analysis ◽  
Comparative Genomic ◽  
Microdeletion Syndrome ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background 12q14 microdeletion syndrome is characterized by low birth weight and failure to thrive, proportionate short stature and developmental delay. The opposite syndrome (microduplication) has not yet been characterized. Our main objective is the recognition of a new clinical entity - 12q14 microduplication syndrome. - as well as confirming the role of HMGA2 gene in growth regulation. Case presentation Array Comparative Genomic Hybridization (CGH), Karyotype, Fluorescence in situ Hybridization, Quantitative-PCR analysis and Whole exome sequencing (WES) were performed in a girl presenting overgrowth and obesity. Array CGH identified a 1.5 Mb 12q14.3 microduplication involving HMGA2, GRIP1, IRAK3, MSRB3 and TMBIM4 genes. Karyotype and FISH showed that duplication was a de novo insertion of 12q14.3 region on chromosome 9p resulting in an interstitial microduplication. Q-PCR confirmed the duplication only in the proband. WES revealed no pathogenic variants. Conclusions Phenotypic comparison with patients with 12q14 microdeletion syndrome showed a reciprocal presentation, suggesting a phenotypically recognizable 12q14 microduplication syndrome as well as confirming the role of HMGA2 gene in growth regulation. It is also indicative that other genes, such as IRAK3 and MSRB3 might have of role in weight gain and obesity.

scholarly journals The evolving role of whole-exome sequencing in the management of disorders of sex development

2021 ◽  
Author(s):  
Yardena Tenenbaum Rakover ◽  
Osnat Admoni ◽  
Gadir Elias-Assad ◽  
Shira London ◽  
Marie Noufi Barhoum ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Sex Development ◽  
Pathogenic Variants ◽  
Extensive Evaluation ◽  
Whole Exome

Objective: Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. Methods: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two patients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. Conclusions: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management, and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Yoshitaka Hiromoto ◽  
Yoshiteru Azuma ◽  
Yuichi Suzuki ◽  
Megumi Hoshina ◽  
Yuri Uchiyama ◽  
...  
Keyword(s):  
De Novo ◽  
Missense Variant ◽  
West Syndrome ◽  
Periventricular Nodular Heterotopia ◽  
Psychomotor Delay ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Epileptic Patients ◽  
Nodular Heterotopia ◽  
Refractory Seizures

AbstractPathogenic FLNA variants can be identified in patients with seizures accompanied by periventricular nodular heterotopia (PVNH). It is unusual to find FLNA aberrations in epileptic patients without PVNH on brain imaging. We report a boy with cryptogenic West syndrome followed by refractory seizures and psychomotor delay. We performed whole-exome sequencing and identified a de novo missense variant in FLNA. It is noteworthy that this patient showed no PVNH. As no other pathogenic variants were found in epilepsy-related genes, this FLNA variant likely caused West syndrome but with no PVNH.

scholarly journals New genes involved in Angelman syndrome-like: expanding the genetic spectrum

2020 ◽  
Author(s):  
Cinthia Aguilera ◽  
Elisabeth Gabau ◽  
Ariadna Ramirez-Mallafré ◽  
Carme Brun-Gasca ◽  
Jana Dominguez-Carral ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Genetic Heterogeneity ◽  
Angelman Syndrome ◽  
De Novo ◽  
System Development ◽  
Neuron System ◽  
Pathogenic Variants ◽  
New Genes ◽  
Whole Exome ◽  
Eeg Abnormalities

AbstractAngelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.

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 Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Guanghui Zhu ◽  
Yu Zheng ◽  
Yaoxi Liu ◽  
An Yan ◽  
Zhengmao Hu ◽  
...  
Keyword(s):  
Clinical Features ◽  
De Novo ◽  
Bone Fractures ◽  
Neurofibromatosis Type ◽  
Clinical Analysis ◽  
Congenital Pseudarthrosis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
New Perspective

Abstract Background Congenital pseudarthrosis of the tibia (CPT) is a rare disease. Some patients present neurofibromatosis type 1 (NF1), while some others do not manifest NF1 (non-NF1). The etiology of CPT, particularly non-NF1 CPT, is not well understood. Here we screened germline variants of 75 CPT cases, including 55 NF1 and 20 non-NF1. Clinical data were classified and analyzed based on NF1 gene variations to investigate the genotype-phenotype relations of the two types of patients. Results Using whole-exome sequencing and Multiplex Ligation-Dependent Probe Amplification, 44 out of 55 NF1 CPT patients (80.0%) were identified as carrying pathogenic variants of the NF1 gene. Twenty-five variants were novel; 53.5% of variants were de novo, and a higher proportion of their carriers presented bone fractures compared to inherited variant carriers. No NF1 pathogenic variants were found in all 20 non-NF1 patients. Clinical features comparing NF1 CPT to non-NF1 CPT did not show significant differences in bowing or fracture onset, lateralization, tissue pathogenical results, abnormality of the proximal tibial epiphysis, and follow-up tibial union after surgery. A considerably higher proportion of non-NF1 patients have cystic lesion (Crawford type III) and used braces after surgery. Conclusions We analyzed a large cohort of non-NF1 and NF1 CPT patients and provided a new perspective for genotype-phenotype features related to germline NF1 variants. Non-NF1 CPT in general had similar clinical features of the tibia as NF1 CPT. Germline NF1 pathogenic variants could differentiate NF1 from non-NF1 CPT but could not explain the CPT heterogeneity of NF1 patients. Our results suggested that non-NF1 CPT was probably not caused by germline NF1 pathogenic variants. In addition to NF1, other genetic variants could also contribute to CPT pathogenesis. Our findings would facilitate the interpretation of NF1 pathogenic variants in CPT genetic counseling.

scholarly journals ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis

2018 ◽  
Vol 33 (13) ◽  
pp. 825-831 ◽  
Author(s):  
Eliza Gordon-Lipkin ◽  
Julie S. Cohen ◽  
Siddharth Srivastava ◽  
Bruno P. Soares ◽  
Eric Levey ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorder ◽  
Failure To Thrive ◽  
Ganglioside Gm3 ◽  
Normal Birth ◽  
Pathogenic Variants ◽  
Gm3 Synthase ◽  
Whole Exome ◽  
Ganglioside Metabolism ◽  
Autosomal Recessive Condition

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

scholarly journals A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

2018 ◽  
Vol 08 (01) ◽  
pp. 010-014 ◽  
Author(s):  
Wafa Alazaizeh ◽  
Asem Alkhateeb
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Frameshift Mutation ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Feeding Difficulties ◽  
Whole Exome

AbstractIntellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

scholarly journals Hypoglycemia and Dandy-Walker variant in a Kabuki syndrome patient: a case report

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Guo ◽  
Yanguo Zhao ◽  
Shuwei Li ◽  
Jingqun Wang ◽  
Xiang Liu
Keyword(s):  
De Novo ◽  
Early Stage ◽  
Novel Mutation ◽  
Molecular Testing ◽  
Kabuki Syndrome ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Chinese Girl ◽  
Neonatal Stage ◽  
Congenital Condition

Abstract Background Kabuki syndrome (KS) is a rare congenital condition with cardinal manifestations of typical facial features, developmental delays, skeletal anomalies, abnormal dermatoglyphic presentations, and mild to moderate intellectual disability. Pathogenic variants in two epigenetic modifier genes, KMT2D and KDM6A, are responsible for KS1 and KS2, respectively. Case presentation A Chinese girl had persistent neonatal hypoglycemia and Dandy-Walker variant. Whole-exome sequencing identified a novel single nucleotide deletion in KMT2D (NM_003482.3 c.12165del p.(Glu4056Serfs*10)) that caused frameshift and premature termination. The mutation was de novo. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is considered pathogenic. The patient was diagnosed with KS by molecular testing. Conclusion A single novel mutation in KMT2D was identified in a KS patients with hypoglycemia and Dandy-Walker variant in the neonatal stage. A molecular test was conducted to diagnose KS at an early stage.

scholarly journals NF1 microdeletion syndrome: case report of two new patients

2019 ◽  
Vol 45 (1) ◽  
Author(s):  
Gregorio Serra ◽  
Vincenzo Antona ◽  
Giovanni Corsello ◽  
Federico Zara ◽  
Ettore Piro ◽  
...  
Keyword(s):  
De Novo ◽  
Present Report ◽  
Pulmonary Stenosis ◽  
Gene Array ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Fish Analysis ◽  
Heterozygous Deletion ◽  
Microdeletion Syndrome ◽  
Molecular Features

Abstract Background 17q11.2 microdeletions, which include the neurofibromatosis type 1 (NF1) gene region, are responsible for the NF1 microdeletion syndrome, observed in 4.2% of all NF1 patients. Large deletions of the NF1 gene and its flanking regions are associated with a more severe NF1 phenotype than the NF1 general population. Case presentation We hereby describe the clinical and molecular features of two girls (aged 2 and 4 years, respectively), with non-mosaic atypical deletions. Patient 1 showed fifteen café-au-lait spots and axillary freckling, as well as a Lisch nodule in the left eye, strabismus, high-arched palate, malocclusion, severe kyphoscoliosis, bilateral calcaneovalgus foot, mild generalized hypotonia, hyperactivity and deficits of speech-related abilities. NF1 genomic rearrangements through multiplex ligation-dependent probe amplification (MLPA) detected an heterozygous deletion of the whole NF1 gene. Array comparative genomic hybridization (a-CGH) analysis defined a 17q11.2 deletion of about 1 Mb (breakpoints at positions 29,124,299 and 30,151,654), which involved different genes (partially CRLF3, ATAD5, TEFM, ADAP2, RNF135, OMG, EVI2B, EVI2A, RAB11FIP4), including NF1. Patient 2 showed growth and developmental delay, supravalvular pulmonary stenosis, twenty-five café-au-lait spots, axillary freckling, craniofacial dysmorphic features, short neck with pterygium, limb abnormalities and foci of neural dysplasia on brain magnetic resonance imaging (MRI). MLPA detected an heterozygous deletion of NF1, which was detailed by a-CGH indicating the positions 29,124,299 and 30,326,958 as its breakpoints, and which included aside from the genes deleted in Patient 1 also COPRS, UTP6 and partially SUZ12. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletions in both cases. Conclusions The present report will likely provide further insights and a better characterization of NF1 microdeletion syndrome.

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