Browsing by Author "Čuturilo, Goran (23469119900)"

Purpose: We sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility. Methods: We retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis. Results: Extended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis. Conclusion: We show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload. © 2018 American College of Medical Genetics and Genomics.

Introduction. GLUT1 deficiency syndrome (GLUT1 DS, OMIM 606777) is a metabolic brain disorder caused by mutations in SLC2A1 gene (chromosome 1) encoding glucose transporter type 1 located on blood-brain membrane. The “classic” phenotype in children includes early onset generalized farmacoresistant epilepsy, developmental delay, complex movement disorders and acquired microcephaly. However, there are milder phenotypes without epilepsy which could be seen in older children. The ketogenic diet is a treatment of choice. Case report. We present a four-year- old female patient with farmacoresistant generalized epilepsy, paroxysmal dystonic posturing, ataxia, hypotonia, developmental delay (motor, attention and speech disturbances), and microcephaly. The genetic testing revealed a novel point mutation at c.156T > A (p.Y52X) in exon 3 of SLC2A1 gene. The patient responded excellent on ketogenic diet. Conclusion. GLUT1 DS is treatable, and likely to be under-diagnosed neurological disorder. The ketogenic diet is resulting in good control of seizures in the patients, and it has certain benefit for the neurodevelopmental disability. Apstrakt Uvod. GLUT1 sindrom deficijencije (GLUT1 DS, OMIM 606777) je metaboličko oboljenje mozga uzrokovano mutacijom u SLC2A1 genu (hromozom 1) koji kodira transporter glukoze tip 1 lokalizovan na krvno-moždanoj barijeri. “Klasični” fenotip kod dece uključuje ranu pojavu generalizovane farmakorezistentne epilepsije, usporen psihomotorni razvoj, poremećaje pokreta i stečenu mikrocefaliju. Međutim, blaži fenotipovi bez pojave epilepsije mogu se videti i u kasnijem uzrastu. Ketogena dijeta je terapija izbora. Prikaz bolesnika. U radu je prikazana devojčica, uzrasta četiri godine sa farmakorezistentnom generalizovanom epilepsijom, paroksizmalnim distonijama, ataksijom, hipotonijom, usporenim razvojem (poremećajima motorike, pažnje i govora) i mikrocefalijom. Genetsko testiranje je otkrilo novu tačkastu mutaciju u c.156T > A (p.Y52X) na egzonu 3 SLC2A1 gena. Kod bolesnice je primećeno poboljšanje u kliničkom nalazu na primenu ketogene dijete. Zaključak. GLUT1 DS je lečiva neurološka bolest, koja je verovatno nedovoljno prepoznata. Ketogena dijeta dovodi do povoljne kontrole napada kod dece, a doprinosi izvesnom poboljšanju u neurološkom nalazu. © 2019, Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. Results: Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. Conclusion: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease. © 2022 American College of Medical Genetics and Genomics

Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome. Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its’ paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly. In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly. © 2018 Elsevier Masson SAS

Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome. Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its’ paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly. In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly. © 2018 Elsevier Masson SAS