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

SYNE1 related cerebellar ataxia presents with variable phenotypes in a consanguineous family from Turkey

SYNE1 related autosomal recessive cerebellar ataxia type 1 (ARCA1) is a late-onset cerebellar ataxia with slow progression originally demonstrated in French-Canadian populations of Quebec, Canada. Nevertheless, recent studies on SYNE1 ataxia have conveyed the condition from a geographically limited pure cerebellar recessive ataxia to a complex multisystem phenotype that is relatively common on the global scale. To determine the underlying genetic cause of the ataxia phenotype in a consanguineous family from Turkey presenting with very slow progressive cerebellar symptoms including dysarthria, dysmetria, and gait ataxia, we performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in two affected siblings. We identified a homozygous variant in SYNE1 (NM_033071.3: c.13086delC; p.His4362GlnfsX2) in all four affected siblings. This variant presented herein has originally been associated with only pure ataxia in a single case. We thus present segregation and phenotypic manifestations of this variant in four affected family members and further extend the pure ataxia phenotype with upper motor neuron involvement and peripheral neuropathy. Our findings in turn established a precise molecular diagnosis in this family, demonstrating the use of WES combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes

A survey of patient preparation and technique of ultrasound-guided prostate biopsy: A multicenter study og urooncological association [Ultrasonografi k?lavuzlugunda yap?lan prostat biyopsisinde hasta haz?rl?g? ve teknik anketi: Üroonkoloji dernegi çcok merkezli çal?şmas?]

Introduction: Ultrasound-guided prostate biopsy is the standard method for the diagnosis of prostate cancer. The aim of the present survey is to assess the variability in patient preparation and technique of ultrasound-guided prostate biopsy among Turkish Urologists. Materials and Methods: In July 2004, a questionnaire was sent out to e-mail addresses of the members of Urooncological Association, asking about the details of prostate biopsy protocol of the members. The survey consisted of multiple choice questions about the patient preparation and prostate biopsy technique. Responses were acquired via e-mail and analyzed in detail. Results: Thirty two urologists from 24 centers responded. The biopsy procedure was performed by the urologist only in 54.16% of the centers, both urologist and radiologist in 37.5%, and radiologist only in 8.33%. Transrectal route was the most common method for ultrasound-guided prostate biopsy. A half of the responders performed biopsy when PSA was greater than 4 ng/ml. All of the centers administered antibiotic and a half of them used enema before the procedure. Approximately 37% of responders did not administer any type of analgesia, but 29.1% of all responders administered a periprostatic nerve block for reducing pain during the procedure. Most urologists obtained 10 or 12 biopsy cores and only 20.8% of them obtained routine transitional zone biopsy during the initial biopsy session. Conclusion: This survey demonstrated that patient preparation and technique of ultrasound-guided prostate biopsy is not standardized among Turkish Urologists, and a guideline on prostate biopsy is needed