Sibel A Ugur Iseri

Istanbul University · Institute of Experimental Medicine

Rare disease patients constitute a significant part of the healthcare system of all countries. However, the information on the experiences during disease processes and daily life of rare disease patients is still limited. So far, there is a small number of studies conducted in Türkiye, and they mainly cover specific issues like education or anxiety...

Background Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, i...

Triggering or modulation of seizures and rhythmic EEG patterns by external stimuli are well-known with the most common clinical appearance of stimulus induced periodic discharges (SI- PDs) patterns which are elicited by physical or auditory stimulation. However, stimulus terminated periodic discharges (ST-PDs), in other words, the periodic discharg...

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological disease with childhood or adult onset. It is a subtype of clinically and genetically heterogeneous group of disorders, collectively known as neurodegeneration with brain iron accumulation . MPAN is generally associated with biallelic pathogenic variants in C19...

Lafora disease (LD) is a severe form of progressive myoclonus epilepsy inherited in an autosomal recessive fashion. It is associated with biallelic pathogenic variations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The disease usually starts with adolescent onset seizures followed by progressive dementia, refractory status epil...

Juvenile myoclonic epilepsy (JME), characterized by predominating myoclonic seizures, is one of the most common forms of genetic generalized epilepsy. Genetic studies in JME reported susceptibility associated with EFHC1 gene. A 26-year-old male patient was admitted to our epilepsy outpatient clinic unit with one generalized tonic-clonic seizure and...

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 epilep...

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 epilep...

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients rema...

Intellectual disability (ID) is a genetically heterogeneous neurodevelopmental disorder characterised by significantly impaired intellectual and adaptive functioning. ID is commonly syndromic and associated with developmental, metabolic and/or neurological findings. Autosomal recessive ID (ARID) is a significant component of ID especially in the pr...

Genetic generalized epilepsies (GGE) are genetically determined, as their name implies and they are clinically characterized by generalized seizures involving both sides of the brain in the absence of detectable brain lesions or other known causes. GGEs are yet complex and are influenced by many different genetic and environmental factors. Methylat...

The most significant 10 pathways identified through the genome-wide family-pool analysis. (DOCX)

List of differentially methylated genes within neurotrophin and cancer pathways along with their description and associated phenotypes. The data is exported via BioMart tool of ENSEMBL. (XLS)

Final outcome of probe and quality filtering steps. 25263 probes and 3 samples were removed from further analyses. (TIF)

PANOGA identified the KEGG ‘MAPK Signaling pathway’ from trio based genome-wide DNA methylation dataset. The pathway is dual-colored on the gene level using epileptic and healthy groups. Rescaled beta values are colored from green to red using the new (-1, 1) range. Epileptic group is represented on the left half and healthy group on the right half...

PANOGA identified the KEGG focal adhesion pathway from trio based genome-wide DNA methylation dataset. The pathway is dual-colored on the gene level using epileptic and healthy groups. Rescaled beta values are colored from green to red using the new (-1, 1) range. Epileptic group is represented on the left half and healthy group on the right half o...

PANOGA identified the KEGG ‘T Cell Receptor (TCR) Signaling Pathway’ from trio based genome-wide DNA methylation dataset. The pathway is dual-colored on the gene level using epileptic and healthy groups. Rescaled beta values are colored from green to red using the new (-1, 1) range. Epileptic group is represented on the left half and healthy group...

Clinical features of father-mother-offspring trios. CAE; childhood absence epilepsy, EEG; electroencephalography, F; female, GGE; Genetic generalized epilepsy, GSWD; generalized spike and wave discharges, GTCS; generalized tonic-clonic seizure, IPS; intermittent photic stimulation, JAE; juvenile absence epilepsy, JME; juvenile myoclonic epilepsy, M...

Trio-based pathways for genome-wide analysis along with the number of trios, in which that particular pathway was identified. (DOCX)

PANOGA identified the KEGG metabolic pathway from trio based genome-wide DNA methylation dataset. The pathway is dual-colored on the gene level using epileptic and healthy groups. Rescaled beta values are colored from green to red using the new (-1, 1) range. Epileptic group is represented on the left half and healthy group on the right half of the...

PANOGA identified the KEGG ‘Chronic Myeloid Leukemia (CML) Pathway’ from trio based genome-wide DNA methylation dataset. The pathway is dual-colored on the gene level using epileptic and healthy groups. Rescaled beta values are colored from green to red using the new (-1, 1) range. Epileptic group is represented on the left half and healthy group o...

The most significant 10 pathways identified through the promoter specific family-pool analysis. (DOCX)

Trio-based pathways for promoter specific analysis along with the number of trios, in which that particular pathway was identified. (DOCX)

Control of bisulphite conversion with RnBeads package. The samples indicated by the blue arrow are 6929726053_R05C01, 6929726054_R01C02 and 6929726054_R03C02 in Trio4 and Trio7, respectively. (TIF)

Differential methylation analysis via T-test. (A) Unsupervised hierarchical clustering of healthy (orange) and epileptic (green) individuals for all probes based on their beta values. The heatmap displays only CpG islands with the highest variance across all samples. Red color indicates beta values in the range of 0–0.5 (hypomethylation); blue colo...

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals...

Introduction: Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-associated neurodegeneration (MPAN); and spastic paraplegia type 43 (SPG43). MPAN is an orphan disease, which presents with spasticity, dystonia, peripheral nerve involvement, and dementia. The pattern of iron accumulation on br...

Aims . In addition to a complex inheritance pattern in genetic generalized epilepsy (GGE) syndromes, some studies have recently identified SLC2A1 variants which lead to glucose transporter type 1 ( GLUT1 ) defects, in patients diagnosed with GGE. Here, we investigated the possible role of SLC2A1 variants in GGE patients with eyelid myoclonia (EM) w...

Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal storage disorder involving the white matter of the peripheral and the central nervous systems. It is caused by a deficiency of galactocerebrosidase enzyme activity. The most common manifestation is the classical early onset KD that leads to patient’s loss before...

Hereditary spastic paraplegias (HSPs) are a group of genetic disorders resulting in pyramidal tract impairment, predominantly in lower limbs. KIF1C gene has recently been identified as one of the genetic causes of HSP and associated with pure or complicated HSP. We present three patients with complicated HSP from two unrelated families, who had ear...

Abstract: Introduction: The FBXO38 gene encodes a large protein that contains an F-box domain, which acts as a transcriptional co-activator of the Krueppel-like factor 7. FBXO38 may also be participated in protein ubiquitination. Heterozygous FBXO38 variations have been implicated in distal hereditary motor neuronopathy type IID (HMN2D) with autoso...

Objectives: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available i...

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 mult...

Abstract Sandhoff disease (SD) is a fatal, autosomal recessive lysosomal storage disease. Mutations in HEXB gene cause neuronal damage and SD due to accumulation of GM2 ganglioside. As ganglioside accumulates in the basal ganglia and white matter abnormalities occur, the T2 hypointensities of the basal ganglia, especially those of the thalamus, bec...

Objective: Pantothenate kinase-associated neurodegeneration (PKAN) is caused by mutations of the pantothenate kinase 2 (PANK2) gene. The major clinical sign of PKAN is dystonia and the eye-of-the-tiger pattern on the MRI has been a clue for the diagnosis. We aim to discuss clinical and genetic findings of 22 PKAN patients from 13 families. Method...

Anophthalmia, microphthalmia, and coloboma are a genetically heterogeneous spectrum of developmental eye disorders and affect around 30 per 100,000 live births. OLFM2 encodes a secreted glycoprotein belonging to the noelin family of olfactomedin domain-containing proteins that modulate the timing of neuronal differentiation during development. OLFM...

Istanbul University Aziz Sancar Institute for Experimental Medicine coordinates a project namely ”Investing in the Future: BIOBANK” project which has been granted by Istanbul Development Agency under ”2015 Innovative Istanbul” Financial support program. The project aims to consolidate good practices for biobanking activities. Accordingly, the proje...

Combined analysis of homozygosity mapping and whole exome sequencing (WES) are powerful tool to detect pathogenic variants associated with recessive disorders. Herein, WES and SNP array used for clarifying delayed motor mental development (DMMD). We also conducted genetic test for Unverricht-Lundborg Disease (ULD) in family for different individual...

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative condition. Major clinical features include progressive dystonia, pigmentary retinopathy, spasticity, and cognitive decline. The typical MRI sign of the disease, known as "eye-of-the-tiger", is what makes differential diagnosis possible. We here describe a 16-year-ol...

Objective We previously found by performing sensory-motor integration (SMI) studies on sedentary subjects that there were less short latency afferent inhibition and higher facilitation after basketball shooting exercises which partially subsided after exercising for five days. We herein present the effect of brain-derived neurotrophic factor (BDNF)...

Introduction: Combined analysis of homozygosity mapping and whole exome sequencing (WES) has served as a powerful tool to detect pathogenic variants associated with recessive disorders. Herein, we applied a two-step approach,where linkage analysis and homozygosity mapping were used to limit exome variants to specific chromosomal regions. Material a...

Introduction: Autosomal Dominant Lateral Temporal Epilepsy (ADLTE) is characterized by focal seizures with a typical involvement of auditory aura. Auditory symptoms occur during seizures that are produced by the primary or association auditory cortices within the lateral temporal lobe. The disea- se may onset both in juvenile and adult terms, where...

The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.

Amaç: Yeni nesil dizileme (YND) teknolojileri ile bir bireyin tüm genom verisi elde edilebilmektedir. Genom verisinin farklı biyolojik temeller gözetilerek analizi ile resesif hastalıkların çözümü sağlanabilir. Bu çalışmada aynı atadan gelmiş koromozomların oluşturduğu homozigot bölgeleri tespit eden, yeni bir program geliştirilmiştir. Yöntem: Homo...

Cerebellar ataxias are characterized by incoordination and unsteadiness of movement due to cerebellar dysfunction. In this study, we analyzed a con- sanguineous family with 4 affected individuals presenting very slowly pro- gressive cerebellar symptoms including dysartria, dysmetria and gait ataxia. All 4 affected and 3 unaffected members from this...

a wide range of neurologic abnormalities. Heterozygous mutations in gene SLC2A1 (GLUT1) have been implicated in Glut1-DS, which encodes Glut1-a major glucose transporter in the mammalian blood-brain barrier. We analyzed SLC2A1 in a Turkish patient with early onset infantile seizu- res, microcephaly, intellectual disability, ataxia, dyskinetic cereb...

Amaç: İdiyopatik Jeneralize Epilepsiler (İJE) toplumun % 0.3’ünü etkiler ve epilepsilerin %30-40’ını oluşturur. Aile ve ikiz çalışmalarında İJE etiyolojisinde genetik faktörle- rin önemi vurgulanmasına rağmen ancak küçük bir kısmın- da ilişkili genler veya kromozom bölgeleri gösterilebilmiş- tir. Bunun sebebi İJE’de yaygın kalıtım modelinin komplek...

Expression analysis of apoptosis related genes in human hippocampal sclerosis.

Epilepsy is a complex neurological disorder that affects 1% of the world’s population. Among different forms of epilepsies, idiopathic generalized epilepsies (IGE) are characterized by bilateral and synchronous generalized seizures in the absence of detectable brain lesions or metabolic abnormalities. Thus, the primary etiology for this disorder is...

Mezyal Temporal Lob Epilepsisi Patogenezinde Apoptoza Yol Açan Genlerin Ekspresyonlarının Araştırılması.

We present a family afflicted with a novel autosomal recessive disease characterized by progressive intellectual disability, motor dysfunction and multiple joint contractures. No pathology was found by cranial imaging, electromyography and muscle biopsy, but electron microscopy in leukocytes revealed large vacuoles containing flocculent material. W...

The authors present three patients from a consanguineous family afflicted with novel recessive myoclonic epilepsy characterized by very early onset and a steadily progressive course. The onset is in early infancy, and death occurs in the first decade. In addition to various types of myoclonic seizures, episodic phenomena such as dystonias, posticta...

Cone-rod dystrophies are inherited retinal dystrophies that are characterized by progressive degeneration of cones and rods, causing an early decrease in central visual acuity and colour vision defects, followed by loss of peripheral vision in adolescence or early adult life. Both genetic and clinical heterogeneity are well known. In a family with...

Mutations in the visual system homeobox 2 gene (VSX2, also known as CHX10), which encodes a retinal transcription factor from the paired homeobox family, have been implicated in recessive isolated microphthalmia. In this study, we use genome-wide single nucleotide polymorphism homozygosity mapping in unrelated small consanguineous pedigrees and a c...

FOXE3 is a lens-specific transcription factor with a highly conserved forkhead domain previously implicated in congenital primary aphakia and anterior segment dysgenesis. Here, we identify new recessive FOXE3 mutations causative for microphthalmia, sclerocornea, primary aphakia, and glaucoma in two extended consanguineous families by SNP array geno...

Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity in the lower limbs. They are clinically heterogeneous, and pure forms as well as complicated forms with other accompanying clinical findings are known. HSPs are also genetically heterogeneous. We performed clinical and genetic studies in a consanguineous family with f...

Split-Hand/Foot Malformation (SHFM) is a complex limb malformation affecting the central rays of the autopod. We studied a large consanguineous kindred afflicted with autosomal recessive SHFM. Twelve affected members had central feet reductions with or without hand involvement while the remaining one had the mildest phenotype and atypical SHFM. We...

Hypomyelination and congenital cataract is a recently reported autosomal recessive white matter disorder characterized by hypomyelination of the central and peripheral nervous systems, progressive neurological impairment and congenital cataract and caused by mutations in gene DRCTNNB1A. Here we report a large intragenic deletion that does not lead...

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. We first identified a PAM locus by homozygosity mapping to 4p15, then identified, by a candidate-gene approach, the gene responsible for the disease as SLC34A2 (the type IIb sodium-phosphate cotransporter g...

We report six patients with Cockayne syndrome type B without photosensitivity. The patients are from the same inbred family and exhibit variable clinical features. The main clinical manifestations were progressive encephalopathy including intracranial calcification and white-matter lesions, dwarfism without growth hormone deficiency, senile appeara...

Hyaline body myopathy is a rare congenital disease with distinctive histopathological features. We performed homozygosity mapping in a family with two affected sibs and identified a gene locus with a maximum homozygosity region of 5.35 centi Morgans or 5.59 Megabases at chromosome 3p22.2-p21.32. The best candidate responsible for the disease is a n...

Seckel syndrome (SCKL) is a rare disease with wide phenotypic heterogeneity. A locus (SCKL1) has been identified at 3q and another (SCKL2) at 18p, both in single kindreds afflicted with the syndrome. We report here a novel locus (SCKL3) at 14q by linkage analysis in 13 Turkish families. In total, 18 affected and 10 unaffected sibs were included in...