Phenotypic and Genotypic Analysis of Hereditary Ataxia Patients in Sakarya City, Turkey

Conclusion: Hereditary ataxias are rare neurodegenerative disorders. Large genetic pool, ethnic and local differences complicate diagnosing even further. Our study contributes to the literature by reflecting phenotypic and genotypic characteristics of hereditary SCA patients in our region and reporting rare hereditary ataxia genotypes

Polygenic burden in focal and generalized epilepsies

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japaneseancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64 710-15; Cleveland: P = 2.85 710-4; Finnish-ancestry Epi25: P = 1.80 710-4) or population controls (Epi25: P = 2.35 710-70; Cleveland: P = 1.43 710-7; Finnish-ancestry Epi25: P = 3.11 710-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 710-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74 710-19; Cleveland: P = 1.69 710-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60 710-15; Cleveland: P = 1.39 710-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment

Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Dentatorubral pallidoluysian atrophy in a Turkish family

Dentatorubral pallidoluysian atrophy is a neurodegenerative disease that generally presents in adulthood. Although rare, it can be observed in childhood due to extreme expansion of the triplet repeat size during spermatogenesis. The diagnosis in childhood is very difficult in the absence of family history. Here we describe a 12-year-old girl with dentatorubral pallidoluysian atrophy who presented with progressive myoclonic epilepsy and ataxia. Family history exhibited similarly affected cases on the paternal side. Molecular testing for dentatorubral pallidoluysian atrophy revealed abnormal "cytosine-adenine-guanosine" expansion in the atrophin-1 gene

Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient. EMG showed demyelinating sensorimotor polyneuropathy in another patient. The GAA expansion-negative 11-year-old female patient had mental-motor retardation, epilepsy, and ataxia. None of the patients had significant cardiac symptoms. Description of FRDA families with different ethnic backgrounds may assist in identifying possible phenotypic and genetic features of the disease. Furthermore, the genetic heterogeneity observed in this family draws attention to the difficulty of genetic counseling in an inbred population and to the need for genotyping all affected members before delivering comprehensive genetic counseling

Case Report Atypical Features in a Large Turkish Family Affected with Friedreich Ataxia

Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient. EMG showed demyelinating sensorimotor polyneuropathy in another patient. The GAA expansion-negative 11-year-old female patient had mental-motor retardation, epilepsy, and ataxia. None of the patients had significant cardiac symptoms. Description of FRDA families with different ethnic backgrounds may assist in identifying possible phenotypic and genetic features of the disease. Furthermore, the genetic heterogeneity observed in this family draws attention to the difficulty of genetic counseling in an inbred population and to the need for genotyping all affected members before delivering comprehensive genetic counseling

FBX07-R498X mutation: Phenotypic variability from chorea to early onset parkinsonism within a family

Objective: FBXO7 mutations (PARK 15), first reported in 2008, are among the monogenic causes of early-onset parkinsonism. Classically, PARK 15 was suggested to correspond to previously described pallido-pyramidal syndrome. Here, we report clinical and genetic findings in a unique family of Kurdish origin with an FBXO7 mutation and presenting with diverse clinical phenotypes