scholarly journals Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

2019 ◽  
Vol 40 (12) ◽  
pp. 2270-2285 ◽  
Author(s):  
Suzanna G.M. Frints ◽  
Friederike Hennig ◽  
Roberto Colombo ◽  
Sebastien Jacquemont ◽  
Paulien Terhal ◽  
...  
Keyword(s):  
De Novo ◽  
Arthrogryposis Multiplex Congenita ◽  
Variable Phenotype

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.

De novo pathogenic variant in TUBB2A presenting with arthrogryposis multiplex congenita, brain abnormalities, and severe developmental delay

2017 ◽  
Vol 173 (10) ◽  
pp. 2725-2730 ◽  
Author(s):  
Resham Ejaz ◽  
Anath C. Lionel ◽  
Susan Blaser ◽  
Susan Walker ◽  
Stephen W. Scherer ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Pathogenic Variant ◽  
Arthrogryposis Multiplex Congenita ◽  
Brain Abnormalities

De Novo Inverted Duplication Deletion of 4p in a 14-Week-Old Male Fetus Aborted Due to Multiple Anomalies

2020 ◽  
Author(s):  
Paolo Fontana ◽  
Laura Bernardini ◽  
Cinzia Lombardi ◽  
Maria Grazia Giuffrida ◽  
Maria Ciavarella ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Cystic Hygroma ◽  
The Body ◽  
Comparative Genomic ◽  
Male Fetus ◽  
Body Of Knowledge ◽  
Inverted Duplication ◽  
Variable Phenotype

AbstractInverted duplications deletions are rare, complex, and nonrecurrent chromosomal rearrangements associated with a variable phenotype. We described the phenotype and genotype of a 14-week-old male fetus, who was aborted after discovery of multiple anomalies (septal cystic hygroma, open abdominal wall, and a nonidentifiable lower limb). At autopsy, fluorescence in situ hybridization and array comparative genomic hybridization identified an inverted duplication with terminal deletion of 4p [46,XY,der(4)del(p16.3)dup(4)(p15.2p16.3)]. Only five genotypically similar cases have been reported, and we hope our case contribution will add meaningful to the body of knowledge.

scholarly journals Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

2021 ◽  
pp. jmedgenet-2020-107595
Author(s):  
Annie Laquerriere ◽  
Dana Jaber ◽  
Emanuela Abiusi ◽  
Jérome Maluenda ◽  
Dan Mejlachowicz ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Added Value ◽  
Disease Genes ◽  
Arthrogryposis Multiplex Congenita ◽  
Pathogenic Variants ◽  
New Genes ◽  
Whole Exome ◽  
Disease Loci

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria

2016 ◽  
Vol 26 (11) ◽  
pp. 744-748 ◽  
Author(s):  
Gianina Ravenscroft ◽  
Nataliya Di Donato ◽  
Gabriele Hahn ◽  
Mark R. Davis ◽  
Paul D. Craven ◽  
...  
Keyword(s):  
De Novo ◽  
Arthrogryposis Multiplex Congenita

scholarly journals De novo mutations of SCN1A are responsible for arthrogryposis broadening the SCN1A-related phenotypes

2020 ◽  
pp. jmedgenet-2020-107166
Author(s):  
Dana Jaber ◽  
Cyril Gitiaux ◽  
Sophie Blesson ◽  
Florent Marguet ◽  
David Buard ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Motor Development ◽  
Early Onset ◽  
De Novo ◽  
Critical Role ◽  
Dravet Syndrome ◽  
Pathological Examination ◽  
Arthrogryposis Multiplex Congenita ◽  
De Novo Mutations

BackgroundArthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC.MethodsWhole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo.ResultsAMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement.ConclusionWe show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A.

scholarly journals De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

2019 ◽  
Vol 22 (4) ◽  
pp. 797-802 ◽  
Author(s):  
Maria J. Nabais Sá ◽  
Hanka Venselaar ◽  
Laurens Wiel ◽  
Aurélien Trimouille ◽  
Eulalie Lasseaux ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Corpus Callosum ◽  
De Novo ◽  
Severe Intellectual Disability ◽  
Variable Phenotype

The Morphology of the Rat Kidney Following Folic Acid Administration

1970 ◽  
Vol 28 ◽  
pp. 200-201
Author(s):  
Aline Byrnes ◽  
Elsa E. Ramos ◽  
Minoru Suzuki ◽  
E.D. Mayfield
Keyword(s):  
Folic Acid ◽  
De Novo ◽  
Specific Activity ◽  
Rat Kidney ◽  
Present Report ◽  
Intracellular Localization ◽  
Male Rats ◽  
Renal Hypertrophy ◽  
Electron Microscopic ◽  
Biochemical Alterations

Renal hypertrophy was induced in 100 g male rats by the injection of 250 mg folic acid (FA) dissolved in 0.3 M NaHCO3/kg body weight (i.v.). Preliminary studies of the biochemical alterations in ribonucleic acid (RNA) metabolism of the renal tissue have been reported recently (1). They are: RNA content and concentration, orotic acid-c14 incorporation into RNA and acid soluble nucleotide pool, intracellular localization of the newly synthesized RNA, and the specific activity of enzymes of the de novo pyrimidine biosynthesis pathway. The present report describes the light and electron microscopic observations in these animals. For light microscopy, kidney slices were fixed in formalin, embedded, sectioned, and stained with H & E and PAS.

Early ossicle growth in the regenerating disc of a brittle star

1994 ◽  
Vol 52 ◽  
pp. 364-365
Author(s):  
M. Shlepr ◽  
R. L. Turner
Keyword(s):  
Cell Membrane ◽  
Light Microscopy ◽  
De Novo ◽  
Current Model ◽  
Syncytium Formation ◽  
Brittle Star ◽  
Intracellular Location ◽  
Limited Volume ◽  
Tissue Calcification

Calcification in the echinoderms occurs within a limited-volume cavity enclosed by cytoplasmic extensions of the mineral depositing cells, the sclerocytes. The current model of this process maintains that the sheath formed from these cytoplasmic extensions is syncytial. Prior studies indicate that syncytium formation might be dependent on sclerocyte density and not required for calcification. This model further envisions that ossicles formed de novo nucleate and grow intracellularly until the ossicle effectively outgrows the vacuole. Continued ossicle growth occurs within the sheath but external to the cell membrane. The initial intracellular location has been confirmed only for elements of the echinoid tooth.The regenerating aboral disc integument of ophiophragmus filograneus was used to test the current echinoderm calcification model. This tissue is free of calcite fragments, thus avoiding questions of cellular engulfment, and ossicles are formed de novo. The tissue calcification pattern was followed by light microscopy in both living and fixed preparations.

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