A Novel Homozygous ADCY5 Variant is Associated with a Neurodevelopmental Disorder and Movement Abnormalities.
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ABSTRACT:
SUBMITTER: Kaiyrzhanov R
PROVIDER: S-EPMC8485619 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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A Novel Homozygous <i>ADCY5</i> Variant is Associated with a Neurodevelopmental Disorder and Movement Abnormalities.
Kaiyrzhanov Rauan R Zaki Maha S MS Maroofian Reza R Dominik Natalia N Rad Aboulfazl A Vona Barbara B Houlden Henry H
Movement disorders clinical practice 20210731 7
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Project description:BackgroundWhile recently identified heterozygous PRPF8 variants have been linked to various human diseases, their role in neurodevelopmental disorders (NDDs) remains ambiguous. This study investigates the potential association between homozygous PRPF8 variants and NDDs. Most PRPF8 variants are primarily associated with retinal diseases; however, we analyze a family with multiple members diagnosed with NDDs.MethodsUsing exome sequencing (ES), the cause of behavioral problems and intellectual disabilities (IDs) of two sisters from a consanguineous parents was solved, and the results confirmed by direct sanger sequencing method likewise protein modeling to assess the structural impact of the identified variant on the PRPF8 protein has been done.ResultsES identified a novel homozygous variant, PRPF8 c.257G>T, p.R86M. To the best of our knowledge at the time of writing this manuscript, the mentioned variant has not been reported in relation to NDDs. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant.ConclusionOur findings indicate that the p.R86M variant may disrupt normal protein function by changing its structure and probably its interaction, potentially leading to the observed neurodevelopmental phenotypes. This study highlights the first link between the PRPF8 variant and NDDs, suggesting a distinct role for specific PRPF8 variants in the etiology of NDDs. These results warrant further investigation into the mechanisms by which PRPF8 variants contribute to NDDs, emphasizing the need for comprehensive genetic screening in families with unexplained neurodevelopmental conditions.
| S-EPMC11894437 | biostudies-literature
Project description:Objective: Neurodevelopmental disorder with or without seizure and gait abnormalities (NEDSGA, MIM * 617864) is a newly described autosomal dominant inherited disease caused by a heterozygous variant in the GRIA4 gene. GRIA4 plays an essential role in excitatory synaptic transmission. In this study, we presented the clinical and genetic features of a female patient carrying a novel de novo variant in GRIA4 and further reviewed the previously reported five different patients. Methods: Evaluation of the patient included a detailed history and clinical examination. Trio-whole exome sequencing (WES) was performed to identify pathogenic variants in NEDSGA. Sanger sequencing was further used to validate the variants. Results: We described the clinical features of an infant diagnosed with NEDSGA caused by a GRIA4 variant, who presented with severe developmental delay, limb hypertonia, generalized seizure, retinal hypoplasia, and chorioretinal hyperpigmentation. The patient developed tricuspid regurgitation, and imaging examination revealed a patent foramen ovale. Trio-WES identified a novel de novo heterozygous missense variant c.1918G>T, p.Ala640Ser in the GRIA4 gene. Multiple in silico tools predicted deleterious effects of p.Ala640Ser. Conclusion: A novel heterozygous missense variant in the GRIA4 gene (c.1918G>T) identified in the proband expanded the genotypic and phenotypic spectrum of disorders associated with GRIA4 variants. This is the first NEDSGA case reported in China. Our findings provide valuable information for the differential diagnosis of neonatal onset neurodevelopmental disorders.
| S-EPMC9065404 | biostudies-literature
Project description:BackgroundNext-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in TRAPPC2L, a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis.MethodsWe performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified TRAPPC2L variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein.ResultsA rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in TRAPPC2L was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and in vitro binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11.ConclusionOur data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the TRAPPC2L p.(Ala2Gly) variant.
| S-EPMC7904957 | biostudies-literature
Project description:Compound heterozygous mutations in SHQ1 have been associated with a rare and severe neurological disorder characterized by global developmental delay (GDD), cerebellar degeneration coupled with seizures, and early-onset dystonia. Currently, only five affected individuals have been documented in the literature. Here, we report three children from two unrelated families harboring a homozygous variant in the gene but with a milder phenotype than previously described. The patients had GDD and seizures. Magnetic resonance imaging analyses revealed diffuse white matter hypomyelination. Sanger sequencing confirmed the whole-exome sequencing results and revealed full segregation of the missense variant (SHQ1:c.833 T > C; p.I278T) in both families. We performed a comprehensive in silico analysis using different prediction classifiers and structural modeling of the variant. Our findings demonstrate that this novel homozygous variant in SHQ1 is likely to be pathogenic and leads to the clinical features observed in our patients.
| S-EPMC9944922 | biostudies-literature
Project description:Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a complex neurological phenotype in a consanguineous Pakistani family with four affected members, manifesting lower limb spasticity and weakness, toe walking, pes equinovarus, and a speech disorder. Genome-wide linkage analysis with microsatellite markers delineated chromosome 3q22.2-q24 harboring the disease gene. Whole exome sequencing was performed for two subjects, identifying a homozygous 14-bp frameshift deletion NM_178554.6:c.842_855del; p(Val281GlyfsTer18) in KY. The variant segregated with the phenotype and was absent from public databases and 100 ethnically matched controls. We confirm a novel homozygous KY variant causing a complex neurological phenotype in this family. A review of previously reported KY variants suggests that variants in this gene can cause a spectrum of neurological phenotypes.
| S-EPMC7554104 | biostudies-literature
Project description:Neurodevelopmental disorders are a large group of disorders that affect ~ 3% of children and represent a serious health problem worldwide. Their etiology is multifactorial and includes genetic, epigenetic, and environmental causes. Mounting evidence shows the importance of genetic causes, especially genes involved in the central nervous system development. As recently discovered, the KMT5B gene is related to abnormal activities of the enzymes that regulate histone activity and gene expression during brain development. Pathogenic KMT5B gene variants lead to autosomal dominant, intellectual developmental disorder 51 (OMIM # 617788). Also, reports on patients with additional features suggest that the KMT5B gene alterations lead to multisystem involvement. Here, we report on a male patient with a severe neurodevelopmental disorder caused by a novel KMT5B gene variant inherited from his mother. The patient had severe intellectual disability, absent speech, marked autistic behavior, attention deficit hyperactivity disorder, and different clinical features, including thoracic scoliosis, dysmorphic facial features, and tall stature. In contrast, his mother, with the same KMT5B variant, had mild intellectual disability and some autistic traits (stereotype hand movement). We elucidated pathogenetic mechanisms that could influence phenotype characteristics. Our findings emphasize the importance of a comprehensive clinical and molecular approach to these patients in order to provide optimal health care.
| S-EPMC10668041 | biostudies-literature
Project description:AGAP1 is an Arf1 GAP that regulates endolysosomal trafficking. Damaging variants have been linked to cerebral palsy and autism. We report 3 new individuals with microdeletion variants in AGAP1 . Affected individuals have intellectual disability (3/3), autism (3/3), dystonia with axial hypotonia (1/3), abnormalities of brain maturation (1/3), growth impairment (2/3) and facial dysmorphism (2/3). We investigated mechanisms potentially underlying AGAP1 neurodevelopmental impairments using the Drosophila ortholog, CenG1a . We discovered reduced axon terminal size, increased neuronal endosome abundance, and elevated autophagy at baseline. Given potential incomplete penetrance, we assessed gene-environment interactions. We found basal elevation in phosphorylation of the integrated stress-response protein eIF2α and inability to further increase eIF2α-P with subsequent cytotoxic stressors. CenG1a -mutant flies have increased lethality from exposure to environmental insults. We propose a model wherein disruption of AGAP1 function impairs endolysosomal trafficking, chronically activating the integrated stress response, and leaving AGAP1-deficient cells susceptible to a variety of second hit cytotoxic stressors. This model may have broader applicability beyond AGAP1 in instances where both genetic and environmental insults co-occur in individuals with neurodevelopmental disorders.Summary statementWe describe 3 additional patients with heterozygous AGAP1 deletion variants and use a loss of function Drosophila model to identify defects in synaptic morphology with increased endosomal sequestration, chronic autophagy induction, basal activation of eIF2α-P, and sensitivity to environmental stressors.
| S-EPMC9915612 | biostudies-literature
Project description:Because biallelic SZT2 variants have been reported in patients with neurodevelopmental disorders associated with various degrees of developmental delay, intractable seizures, and distinctive features; this condition is recognized as an autosomal recessive disorder. Previously, eleven patients have been reported and most of them have compound heterozygous SZT2 variants, leading to premature termination. In these patients, all reported variants were unique and there were no common pathogenic variants identified. In this study, we identified a paternal uniparental disomy of chromosome 1 in a patient with a neurodevelopmental disorder associated with severe intellectual disability, intractable epilepsy, autistic features, distinctive features, and transient macrocephaly. This resulted in homozygous patterns through chromosome 1. Among the variants in chromosome 1, a rare SZT2 variant, NM_015284.3:c.6553C>T (p.Arg2185Trp), was selected as a powerful candidate variant in this patient. Although the clinical features of this patient are relatively milder than that reported previously, it may be derived from genetic heterogeneity. This is the first report of a homozygous missense SZT2 variant.
| S-EPMC6290849 | biostudies-literature
Project description:PurposeThis study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.MethodsWe performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.ResultsIn the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells.ConclusionWe established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.
| S-EPMC9905285 | biostudies-literature
Project description:Background: Despite their high lifetime prevalence, major depressive disorder (MDD) is often difficult to diagnose, and there is a need for useful biomarkers for the diagnosis of MDD. Eye movements are considered a non-invasive potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia. However, eye movement deficits in MDD remain unclear. Thus, we evaluated detailed eye movement measurements to validate its usefulness as a biomarker in MDD. Methods: Eye movements were recorded from 37 patients with MDD and 400 healthy controls (HCs) using the same system at five University hospitals. We administered free-viewing, fixation stability, and smooth pursuit tests, and obtained 35 eye movement measurements. We performed analyses of covariance with group as an independent variable and age as a covariate. In 4 out of 35 measurements with significant group-by-age interactions, we evaluated aging effects. Discriminant analysis and receiver operating characteristic (ROC) analysis were conducted. Results: In the free-viewing test, scanpath length was significantly shorter in MDD (p = 4.2 × 10-3). In the smooth pursuit test, duration of saccades was significantly shorter and peak saccade velocity was significantly lower in MDD (p = 3.7 × 10-3, p = 3.9 × 10-3, respectively). In the fixation stability test, there were no significant group differences. There were significant group differences in the older cohort, but not in the younger cohort, for the number of fixations, duration of fixation, number of saccades, and fixation density in the free-viewing test. A discriminant analysis using scanpath length in the free-viewing test and peak saccade velocity in the smooth pursuit showed MDD could be distinguished from HCs with 72.1% accuracy. In the ROC analysis, the area under the curve was 0.76 (standard error = 0.05, p = 1.2 × 10-7, 95% confidence interval = 0.67-0.85). Conclusion: These results suggest that detailed eye movement tests can assist in differentiating MDD from HCs, especially in older subjects.
| S-EPMC8382962 | biostudies-literature