Researcher:
Altunoğlu, Umut

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Umut

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Altunoğlu

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Altunoğlu, Umut

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2017 - 201912020 - 202324

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    Functional loss of ubiquitin-specific protease 14 may lead to a novel distal arthrogryposis phenotype
    (Wiley, 2022) Turgut, Gozde Tutku; Sivrikoz, Tugba Sarac; Toksoy, Guven; Kalayci, Tugba; Karaman, Birsen; Gulec, Cagri; Basaran, Seher; Sayin, Gozde Yesil; Uyguner, Zehra Oya; N/A; N/A; N/A; Altunoğlu, Umut; Avcı, Şahin; Kayserili, Hülya; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; 126174; N/A; 7945
    Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.
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    Skeletal and molecular findings in 51 cleidocranial dysplasia patients from Turkey
    (Wiley, 2021) Berkay, Ezgi Gizem; Elkanova, Leyla; Kalayci, Tugba; Uludag Alkaya, Dilek; Altunoglu, Umut; Cefle, Kivanc; Mihci, Ercan; Nur, Banu; Tasdelen, Elifcan; Bayramoglu, Zuhal; Karaman, Volkan; Toksoy, Guven; Gunes, Nilay; ozturk, Sukru; Palanduz, Sukru; Tuysuz, Beyhan; Uyguner, Zehra Oya; Altunoğlu, Umut; Kayserili, Hülya; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 126174; 7945
    Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29_30insT, c.203delAinsCG, c.423 + 2delT, c.443_454delTACCAGATGGGAinsG, c.505C > T, c.594_595delCTinsG, c.636_637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29_30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort.
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    Prenatal ultrasonographic features in Blomstrand osteochondrodysplasia: antenatal case series confirmed by postmortem radiology and molecular diagnosis
    (John Wiley and Sons Ltd, 2022) Sarac Sivrikoz T.; Kalayci T.; Senturk L.; Karaman V.; Kalelioglu I.H.; Has R.; Uyguner Z.O.; Nishimura G.; N/A; Kayserili, Hülya; Altunoğlu, Umut; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 7945; 126174
    Objective: Blomstrand osteochondrodysplasia (BOCD, MIM #215045) is an ultrarare lethal skeletal dysplasia (LSD) perinatally, characterized by extremely advanced bone maturation, generalized osteosclerosis, and severe tetramicromelia caused by biallelic loss-of-function mutations in the parathyroid hormone receptor-1 gene (PTHR1). We aim to describe prenatal ultrasonographic features in a retrospective fetal case series of BOCD and emphasize the importance of multidisciplinary antenatal evaluation of LSDs to improve the differential diagnosis. Method: Prenatal ultrasound findings of five fetal cases diagnosed with BOCD between 2000 and 2019 in the Prenatal Diagnosis Unit and Medical Genetics were reviewed, along with postmortem examination results and confirmatory molecular results. Results: All fetuses presented with severe sonographic findings of LSDs comprising tetramicromelia, thoracic hypoplasia, and retro-micrognathia. Marked cervical hyperextension was present in three fetuses. Flared metaphyses were prenatally identified in only one fetus. X-rays of four fetuses evaluated postmortem showed advanced bone maturation, generalized osteosclerosis, and dumbbell-like appearance of long bones due to metaphyseal enlargement. Conclusion: The presence of retro-micrognathia along with a protruding tongue and severe metaphyseal flaring can suggest a diagnosis of BOCD, when prenatal ultrasound findings are indicative for LSD. The diagnosis can be ascertained through postmortem clinical and radiological evaluation and/or molecular testing.
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    Expanding the phenotypic spectrum of Alkuraya-Kucinskas syndrome: defining the mildest end
    (Springernature, 2020) Altunoğlu, Umut; Avcı, Şahin; Eraslan, Serpil; Kayserili, Hülya; Çepni, Kardelen; Faculty Member; Faculty Member; Researcher; Faculty Member; PhD Student; School of Medicine; School of Medicine; School of Medicine; School of Medicine; Graduate School of Health Sciences; 126174; N/A; N/A; 7945; N/A
    Alkuraya-Kucinskas syndrome (ALKKUCS, OMIM #617822) is a recently described, ultra-rare autosomal recessive neurodevelopmental disorder characterized by structural, cortical and parenchymal brain abnormalities, global developmental delay/intellectual deficit and joint contractures. The phenotypic spectrum of 15 previously reported cases range from mild-to-moderate intellectual deficit with microcephaly to a phenotype characterized by severe ventriculomegaly and/or brainstem dysgenesis with intrauterine or neonatal death. Only three children survived till childhood. We here report two new ALKKUCS cases from two unrelated consanguineous families. The first patient was presented with antenatal ultrasound findings of severe hydrocephaly, interhemispheric cyst, hydropic changes with cystic hygroma and joint contractures. Pedigree analysis showed two similarly affected siblings and four affected cousins. Postmortem examination was compatible with a lethal contracture phenotype. Whole exome sequencing (WES) revealed a ‘likely pathogenic’ homozygous variant in the KIAA1109 gene. The second patient was consulted at 9 years of age. She had a history of NICU care due to poor sucking/weak swallowing reflex and cardiac arrest in early neonatal period. Clinical findings included mild myopathy of the neck muscles, pes equinovarus, scapula alata and camptodactyly. Identification of a homozygous variant in the KIAA1109 gene, segregating with the phenotype, made the diagnosis of ALKKUCS possible, placing the case to the mildest end of the phenotypic spectrum. Cases we here report highlights the power of WES in identifying genetic etiopathogenesis of rare disorders; and expand the phenotypic spectrum of ALKKUCS.
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    The first case of dyssegmental dysplasia rolland-desbuquois type with a variant in hspg2
    (Springernature, 2020) Kalayci, T.; Balanda, N.; Ferreira, C. R.; N/A; Altunoğlu, Umut; Faculty Member; School of Medicine; 126174
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    A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing
    (John Wiley and Sons Inc, 2023) Bressin, Annkatrin; Shboul, Mohammad; Moreno Traspas, Ricardo; Chia, Poh Hui; Bonnard, Carine; Szenker-Ravi, Emmanuelle; Beillard, Emmanuel; Hojati, Zohreh; Drutman, Scott; Freier, Susanne; El-Khateeb, Mohammad; Fathallah, Rajaa; Casanova, Jean-Laurent; Soror, Wesam; Arafat, Alaa; Mayer, Andreas; Altunoğlu, Umut; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Sarıbaş, Burak; Faculty Member; Faculty Member; Researcher; Researcher; Master Student; School of Medicine; School of Medicine; School of Medicine; N/A; Graduate School of Health Sciences; 126174; 274182; N/A; N/A; N/A
    Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronic TAPT1 mutation (c.1237-52 G>A) that segregated with the disease. Using SI-NET-seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non-coding variants, as well as in illuminating the molecular mechanisms of human diseases. © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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    Three Nance Horan Syndrome families from Turkey; three different approaches for molecular diagnosis
    (Springernature, 2022) Güven, Yeliz; Aksakal, Şermin Dice; Kalaycı, Tuğba; UyGüner, Zehra Oya; Saraçoğlu, Hilal Pırıl; Altunoğlu, Umut; Eraslan, Serpil; Börklü Yücel, Esra; Kayserili, Hülya; Phd Student; Faculty Member; Other; Other; Faculty Member; Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; N/A; 126174; N/A; N/A; 7945
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    Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis
    (Wiley, 2022) Shukla, Anju; Ledig, Susanne; Nayak, Shalini S.; Girisha, Katta Mohan; Kennerknecht, Ingo; Altunoğlu, Umut; Börklü Yücel, Esra; Azaklı, Hülya; Eraslan, Serpil; Kayserili, Hülya; Faculty Member; Other; Researcher; PhD Student; Researcher; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; School of Medicine; Graduate School of Health Sciences; N/A; School of Medicine; Koç University Hospital; Koç University Hospital; Koç University Hospital; N/A; Koç University Hospital; Koç University Hospital; 126174; N/A; N/A; N/A; N/A; 7945
    Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.
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    Mutations in AR or SRD5A2 genes: clinical findings, endocrine pitfalls, and genetic features of children with 46,XY DSD
    (Galenos Yayınevi, 2022) Akcan, Nese; Uyguner, Oya; Bas, Firdevs; Toksoy, Guven; Karaman, Birsen; Abali, Zehra Yavas; Poyrazoglu, Sukran; Aghayev, Agharza; Karaman, Volkan; Bundak, Ruveyde; Basaran, Seher; Darendeliler, Feyza; Altunoğlu, Umut; Avcı, Şahin; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 126174; N/A
    Objective: Androgen insensivity syndrome (AIS) and 5 alpha-reductase deficiency (5 alpha-RD) present with indistinguishable phenotypes among the 46,XY disorders of sexual development (DSD) that usually necessitate molecular analyses for the definitive diagnosis in the prepubertal period. The aim was to evaluate the clinical, hormonal and genetic findings of 46,XY DSD patients who were diagnosed as AIS or 5 alpha-RD. Methods: Patients diagnosed as AIS or 5 alpha-RD according to clinical and hormonal evaluations were investigated. Sequence variants of steroid 5-alpha-reductase type 2 were analyzed in cases with testosterone/dihydrotestosterone (T/DHT) ratio of >= 20, whereas the androgen receptor (AR) gene was screened when the ratio was <20. Stepwise analysis of other associated genes were screened in cases with no causative variant found in initial analysis. For statistical comparisons, the group was divided into three main groups and subgroups according to their genetic diagnosis and T/DHT ratios. Results: A total of 128 DSD patients from 125 non-related families were enrolled. Birth weight SDS and gestational weeks were significantly higher in 5 alpha-RD group than in AIS and undiagnosed groups. Completely female phenotype was higher in all subgroups of both AIS and 5 alpha-RD patients than in the undiagnosed subgroups. In those patients with stimulated T/DHT <20 in the prepubertal period, stimulated T/DHT ratio was significantly lower in AIS than in the undiagnosed group, and higher in 5 alpha-RD. Phenotype associated variants were detected in 24% (n=18 AIS, n=14 5 alpha-RD) of the patients, revealing four novel AR variants (c.94G>T, p.Glu32*, c.330G>C, p.Leu110=; c.2084C>T, p.Pro695Leu, c.2585_2592delAGCTCCTG, p.(Lys862Argfs*16), of these c.330G>C with silent status remained undefined in terms of its causative effects. Conclusion: T/DHT ratio is an important hormonal criterion, but in some cases, T/DHT ratio may lead to diagnostic confusion. Molecular is for the robust of 46,XY DSD Four novel AR variants were identified in our study.
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    Clinical and molecular results of six cases with roberts syndrome: review of cases from Turkey
    (Istanbul Univ, Fac Medicine, Publ Off, 2022) Aslanger, Ayca Dilruba; Kalayci, Tugba; Konur, Esma Nur; Gulec, Cagri; Karaman, Volkan; Toksoy, Guven; Karaman, Birsen; Basaran, Seher; Uyguner, Zehra; Yesil, Gozde; N/A; Avcı, Şahin; Altunoğlu, Umut; Faculty Member; Faculty Member; School of Medicine; School of Medicine; N/A; 126174
    Objective: Roberts syndrome is a rare autosomal recessive disease characterized by limb defects, prenatal onset growth retardation, and craniofacial anomalies. We aimed to compare the clinical and molecular findings of six cases with Roberts syndrome with the previously reported patients from Turkiye and to emphasize that a definitive diagnosis can be made in the intrauterine period with cytogenetic tests in the early period without the need to wait for molecular test results. Materials and Methods: Six cases, diagnosed with Roberts syndrome, in our outpatient clinic of Istanbul University, Istanbul Faculty of Medicine, Medical Genetics Department between 2015-2021, were included in the study. The family history, clinical information, and cytogenetic and molecular findings of the patients were retrospectively reviewed and compared with the cases reported from Turkiye in the literature. G and C-banding techniques and Sanger sequencing of the ESCO2 gene were performed. Results: Pathogenic variants in homozygous in four and compound heterozygous in two patients in the ESCO2 gene were identified. Compound heterozygous c.[417dup];[1131+1G>A] (p.[(Pro140Thrfs(star)8)];[(?)]) in case 1, and c.[1111dup];[760del] (p.[(Thr371Asnfs(star)32)];[(Thr254Leufs(star)13)]) in case 6, homozygous c.1131+1G>A (p.(?)) in case 2, case 3 and case 5, and homozygous c.1111dup (p.(Thr371Asnfs(star)32)) in case 4 were detected. The variants reported in our case series were previously associated with the disease. The first demonstration of the c.760del in a Turkish case contributed to the genetic association of this pathogenic variants with Roberts syndrome Although all the previously reported patients were homozygous, we have detected two patients with compound heterozygous pathogenic alterations from Turkiye indicating that the disease should also be considered in families with no consanguinity.