scholarly journals Muscular and Molecular Pathology Associated with SPATA5 Deficiency in a Child with EHLMRS

2021 ◽  
Vol 22 (15) ◽  
pp. 7835
Author(s):  
Frederik Braun ◽  
Andreas Hentschel ◽  
Albert Sickmann ◽  
Theodore Marteau ◽  
Swantje Hertel ◽  
...  
Keyword(s):  
Molecular Pathology ◽  
Muscle Pathology ◽  
Compound Heterozygous ◽  
Proteomic Profiling ◽  
Mitochondrial Pathology ◽  
Microscopic Studies ◽  
Molecular Etiology ◽  
Relevant Compound ◽  
Mitochondrial Morphogenesis ◽  
Compound Heterozygous Variants

Mutations in the SPATA5 gene are associated with epilepsy, hearing loss and mental retardation syndrome (EHLMRS). While SPATA5 is ubiquitously expressed and is attributed a role within mitochondrial morphogenesis during spermatogenesis, there is only limited knowledge about the associated muscular and molecular pathology. This study reports on a comprehensive workup of muscular pathology, including proteomic profiling and microscopic studies, performed on an 8-year-old girl with typical clinical presentation of EHLMRS, where exome analysis revealed two clinically relevant, compound-heterozygous variants in SPATA5. Proteomic profiling of a quadriceps biopsy showed the dysregulation of 82 proteins, out of which 15 were localized in the mitochondrion, while 19 were associated with diseases presenting with phenotypical overlap to EHLMRS. Histological staining of our patient’s muscle biopsy hints towards mitochondrial pathology, while the identification of dysregulated proteins attested to the vulnerability of the cell beyond the mitochondria. Through our study we provide insights into the molecular etiology of EHLMRS and provide further evidence for a muscle pathology associated with SPATA5 deficiency, including a pathological histochemical pattern accompanied by dysregulated protein expression.

Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia

2021 ◽  
Author(s):  
Sophie Sleiman ◽  
Aren E Marshall ◽  
Xiaomin Dong ◽  
Aziz Mhanni ◽  
Ismaël Alidou-D’Anjou ◽  
...  
Keyword(s):  
Early Onset ◽  
Dopamine Metabolism ◽  
Compound Heterozygous ◽  
Developmental Defects ◽  
Sibling Pairs ◽  
Molecular Etiology ◽  
Neurological Features ◽  
Compound Heterozygous Variants ◽  
Protein Variants ◽  
Ribosome Formation

Abstract SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

scholarly journals Phenotypical and Myopathological Consequences of Compound Heterozygous Missense and Nonsense Variants in SLC18A3

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3481
Author(s):  
Adela Della Marina ◽  
Annabelle Arlt ◽  
Ulrike Schara-Schmidt ◽  
Christel Depienne ◽  
Andrea Gangfuß ◽  
...  
Keyword(s):  
Animal Models ◽  
Molecular Genetic ◽  
Microscopic Investigation ◽  
Muscle Pathology ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Microscopic Studies ◽  
Lipid Aggregates ◽  
The Impact ◽  
Detrimental Impact

Background: Presynaptic forms of congenital myasthenic syndromes (CMS) due to pathogenic variants in SLC18A3 impairing the synthesis and recycling of acetylcholine (ACh) have recently been described. SLC18A3 encodes the vesicular ACh transporter (VAChT), modulating the active transport of ACh at the neuromuscular junction, and homozygous loss of VAChT leads to lethality. Methods: Exome sequencing (ES) was carried out to identify the molecular genetic cause of the disease in a 5-year-old male patient and histological, immunofluorescence as well as electron- and CARS-microscopic studies were performed to delineate the muscle pathology, which has so far only been studied in VAChT-deficient animal models. Results: ES unraveled compound heterozygous missense and nonsense variants (c.315G>A, p.Trp105* and c.1192G>C, p.Asp398His) in SLC18A3. Comparison with already-published cases suggests a more severe phenotype including impaired motor and cognitive development, possibly related to a more severe effect of the nonsense variant. Therapy with pyridostigmine was only partially effective while 3,4 diaminopyridine showed no effect. Microscopic investigation of the muscle biopsy revealed reduced fibre size and a significant accumulation of lipid droplets. Conclusions: We suggest that nonsense variants have a more detrimental impact on the clinical manifestation of SLC18A3-associated CMS. The impact of pathogenic SLC18A3 variants on muscle fibre integrity beyond the effect of denervation is suggested by the build-up of lipid aggregates. This in turn implicates the importance of proper VAChT-mediated synthesis and recycling of ACh for lipid homeostasis in muscle cells. This hypothesis is further supported by the pathological observations obtained in previously published VAChT-animal models.

scholarly journals Novel ARG1 variants identified in a patient with arginase 1 deficiency

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Katsuyuki Yokoi ◽  
Yoko Nakajima ◽  
Toshihiro Yasui ◽  
Makoto Yoshino ◽  
Tetsushi Yoshikawa ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Arginase Activity ◽  
Compound Heterozygous ◽  
Measurement Sensitivity ◽  
Protein Core ◽  
Arginase 1 ◽  
Conserved Domain ◽  
New Variant ◽  
Compound Heterozygous Variants

AbstractWe report a case of a 13-year-old boy with arginase 1 deficiency carrying a new variant in ARG1. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G>A (p.Trp122*)/c.820G>A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.

scholarly journals Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Carla De Angelis ◽  
Alicia B. Byrne ◽  
Rebecca Morrow ◽  
Jinghua Feng ◽  
Thuong Ha ◽  
...  
Keyword(s):  
Cortical Development ◽  
Occipital Cortex ◽  
Compound Heterozygous ◽  
Valuable Insight ◽  
Periventricular Nodular Heterotopia ◽  
Case Presentation ◽  
Malformation Of Cortical Development ◽  
Nodular Heterotopia ◽  
Compound Heterozygous Variants ◽  
Insight Into

Abstract Background Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. Case presentation We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. Conclusion We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.

scholarly journals Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1053
Author(s):  
Jasleen Dhaliwal ◽  
Ying Qiao ◽  
Kristina Calli ◽  
Sally Martell ◽  
Simone Race ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Variable Effect ◽  
Gabaergic Neurotransmission ◽  
High Heritability ◽  
Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

Neonatal-Onset Familial Mediterranean Fever in an Infant with Human Parainfluenza Virus-4 Infection

Neonatology ◽  
2021 ◽  
pp. 1-5
Author(s):  
Alexandre Michev ◽  
Alessandro Borghesi ◽  
Caterina Tretti ◽  
Maddalena Martella ◽  
Amelia Di Comite ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Parainfluenza Virus ◽  
Compound Heterozygous ◽  
Inborn Errors ◽  
Immunological Responses ◽  
Inflammatory Conditions ◽  
Neonatal Onset ◽  
Mediterranean Fever ◽  
Compound Heterozygous Variants ◽  
Human Parainfluenza Virus

Unusual, severe infections or inflammatory episodes in newborns and infants are largely unexplained and often attributed to immature immune responses. Inborn errors of immunity (IEI) are increasingly recognized as the etiology of life-threatening inflammatory and infectious diseases in infancy. We describe a patient with a unique neonatal-onset Familial Mediterranean Fever (FMF) due to compound heterozygous variants in <i>MEFV</i>, presenting as pleuritis following human parainfluenza virus-4 infection. Diagnostic challenges of FMF in infancy include the interpretation of the attacks as infectious episodes. Newborns and infants with acute, recurrent, or chronic, unusually severe infectious or inflammatory conditions should be screened for IEI, including both disorders with defective immunological responses and autoinflammatory disorders.

scholarly journals Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Chunli Wei ◽  
Ting Xiao ◽  
Jingliang Cheng ◽  
Jiewen Fu ◽  
Qi Zhou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
The Novel ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Compound Heterozygous Variants ◽  
Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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