Aug 2026· Frontiers in Genetics· Vol 17· 0 citations· 20 references
Medicine
TL;DR
This variant is the first reported, enriching the database and providing additional evidence to support genetic counselling and prenatal diagnosis, and is the first reported to lead to exon 2 skipping of GRIA3.
Abstract
Background The GRIA3 gene is located on the X chromosome and encodes a subunit (GluR3) of the a-amino-3- hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). The pathogenic variants of GRIA3 are mostly associated with neurodevelopmental disorders. Patients were overwhelmingly male and presented mainly with intellectual disability, dystonia, epilepsy and other symptoms. Methods In this study, we reported a pedigree that carried a novel splicing site variant of GRIA3 (c.268 + 1G>C) by whole exome sequencing (WES) and co-segregation analysis. Three affected family members (two males and one female) not only showed intellectual disability but also presented significant psychiatric symptoms and spatial memory deficits. The minigene assay further confirmed that this variant lead to exon 2 skipping. Results According to ACMG guidelines, We reclassified previously variant of unknown significance (VUS) into “likely pathogenic” through co-segregates analysis and minigene assay. Conclusion It is worth noting that, unlike previous reports, our patients mainly manifested as intellectual disability combined with psychiatric symptoms, expanding the known phenotypic spectrum of GRIA3 gene. Moreover, this variant is the first reported, enriching the database and providing additional evidence to support genetic counselling and prenatal diagnosis.
Objective: To study the Progressive myoclonic epilepsies (PME) that is genetic disorders resulting from mutations in different genes, all characterized by the early onset of myoclonic seizures, and cognitive decline. The Potassium Channel Tetramerization Domain Containing seven (KCTD7) gene encodes for the BRC (broad complex), ttk (tramtrack), and bab/pox virus, and zinc finger domain, containing KCTD7 protein.
Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR). The affected patient, a three-year-old Saudi female born to consanguineous parents, she underwent laboratory tests, EEG assessments, and Whole-Exome Sequencing (WES).
Results: Our results showed a novel five base pair deletion that was detected in homozygous state in the KCTD7 gene. Both the unaffected parents showed heterozygous mutation of the KCTD7 gene. Segregation analysis via Sanger sequencing supported the existence of the homozygous splice donor variant in NM_153033.4:c.493+2_493+6delTGA of KCTD7 gene in the patient.
Conclusion: The mutation is not reported in the literature yet; the particular phenotype that was observed in our patient is comparable to the ones that are described in the KCTD7 related pathologies, combined with segregation analysis indicating both parents carried the variant heterogeneously present is a strong indication that the identified mutation consists of probably pathogenic mutation. This finding will further increase our insight of the genetic basis of PMEs and role of KCTD7 gene mutations in Saudi population.
S. Alharazy, Peter Natesan Pushparaj, Rose Jelani et al.· Pakistan Journal of Medical...· 0 citations
The biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders is supported, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs.
M. Vinci, M. Figura, A. Musumeci et al.· Genes· 0 citations
The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 0 citations
The findings support the pathogenicity of this variant and further expand the pathogenic variant spectrum of the PPP2CA gene, and the observed genotype–phenotype correlation provides valuable information for prognosis and genetic counseling.
Lei Xu, Yanfeng Shen, Guixiang Zhang· Frontiers in Psychiatry· 0 citations
Background. The VPS35 p.D620N variant causes autosomal dominant Parkinson's disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods. We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results. The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions. While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.
S. Glendinning, J. A. Arbelo Gonzalez, L. Diaz-Feliz et al.· medRxiv· 0 citations
This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.
Rina Su, Lei Zhu, Lin Jiang et al.· Frontiers in Neuroscience· 0 citations