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 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.

Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

2022 ◽  
pp. 097321792110688
Author(s):  
Francisco Ribeiro-Mourão ◽  
Ana Vilan ◽  
Sara Passos-Silva ◽  
Fernando Silveira ◽  
Miguel Leão ◽  
...  
Keyword(s):  
De Novo ◽  
Bone Fractures ◽  
Muscular Atrophy ◽  
Hip Dislocation ◽  
Arthrogryposis Multiplex Congenita ◽  
Pathogenic Variants ◽  
Genetic Abnormalities ◽  
Heterozygous Variant ◽  
Fetal Movements ◽  
Intrafamilial Variability

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

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 Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

2020 ◽  
Vol 21 (2) ◽  
pp. 516 ◽  
Author(s):  
Lisa Gianesello ◽  
Monica Ceol ◽  
Loris Bertoldi ◽  
Liliana Terrin ◽  
Giovanna Priante ◽  
...  
Keyword(s):  
Dent Disease ◽  
Low Molecular Weight ◽  
Disease Genes ◽  
Loss Of Function ◽  
Clcn5 Gene ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Low Molecular Weight Proteins ◽  
Clcn5 Mutations

Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

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 A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 92
Author(s):  
Hesham Aldhalaan ◽  
Albandary AlBakheet ◽  
Sarah AlRuways ◽  
Nouf AlMutairi ◽  
Maha AlNakiyah ◽  
...  
Keyword(s):  
Clinical Features ◽  
Phenotypic Characteristics ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Spastic Quadriplegia ◽  
Novel Variant ◽  
Sanger Sequence ◽  
Saudi Family ◽  
Neurodevelopmental Impairment ◽  
Renal Abnormalities

Pathogenic variants in GEMIN4 contribute to a hereditary disorder characterized by neurodevelopmental features, microcephaly, cataracts, and renal abnormalities (known as NEDMCR). To date, only two homoallelic variations have been linked to the disease. Moreover, clinical features associated with the variants have not been fully elucidated yet. Here, we identified a novel variant in GEMIN4 (NM_015721:exon2:c.440A>G:p.His147Arg) in two siblings from a consanguineous Saudi family by using whole exome sequencing followed by Sanger sequence verification. We comprehensively investigated the patients’ clinical features, including brain imaging and electroencephalogram findings, and compared their phenotypic characteristics with those of previously reported cases. In silico prediction and structural modeling support that the p.His147Arg variant is pathogenic.

scholarly journals Coffin-Lowry preprint 2018

2018 ◽  
Author(s):  
Paolo Moretti
Keyword(s):  
Family History ◽  
Clinical Features ◽  
De Novo ◽  
Severe Disease ◽  
Immunosuppressive Treatment ◽  
Pathogenic Variant ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

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 When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1636
Author(s):  
Camille Cenni ◽  
Luke Mansard ◽  
Catherine Blanchet ◽  
David Baux ◽  
Christel Vaché ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Case Report ◽  
De Novo ◽  
Panel Analysis ◽  
Adult Onset ◽  
Childhood Onset ◽  
Model Case ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Neonatal Thrombocytopenia

We describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child’s mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child’s father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: MYH9, MYO7A and ACTG1. The thrombocytopenia in the child and her mother is explained by the MYH9 variant. The post-lingual HL in the paternal branch is explained by the MYO7A variant, absent in the proband, while the congenital HL of the child is explained by a de novo ACTG1 variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected.

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