Research Project: Kraniofasiyal Malformasyonlara Klinik ve Genetik Yaklaşım
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Contributors
Funders
ID
TB.00235
Authors
Kayserili, Hülya
Faculty Member
Publications
A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome
(BioMed Central, 2016) Kayserili, Hülya; Oud, M.M.; Bonnard, C.; Mans, D.A.; Altunoğlu, U.; Tohari, S.; Ng, A.Y.J.; Eskin, A.; Lee, H.; Rupar, C.A.; Wagenaar, N.P.; Wu, K.M.; Lahiry, P.; Pazour, G.J.; Nelson, S.F.; Hegele, R.A.; Roepman, R; Venkatesh, B.; Siu, V.M.; Reversade, B.; Arts, H.H.; School of Medicine; Yes; SCHOOL OF MEDICINE
Background: Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology. Results: Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells. Conclusions: Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.
Fetal skeletal dysplasia cohort of a single tertiary referral center in Istanbul, Turkey
(Wiley, 2023) Altunoğlu, Umut; Avcı, Şahin; Kayserili, Hülya; Kalayci, Tugba; Esmer, Aytul Corbacioglu; Sivrikoz, Tugba Sarac; Karaman, Birsen; Kalelioglu, Ibrahim; Has, Recep; Uyguner, Zehra Oya; Yuksel, Atil; Basaran, Seher; School of Medicine; Yes; SCHOOL OF MEDICINE
We report on 314 fetal cases from 297 unrelated families with skeletal dysplasia evaluated in the postmortem period from 2000 to 2017 at a single clinical genetics center in Istanbul, Turkey. The definite diagnostic yield was 40% during the prenatal period, while it reached 74.5% when combined with postmortem clinical and radiological evaluation. Molecular analyses were performed in 25.5% (n: 76) of families, and 21 novel variants were identified. Classification according to International Skeletal Dysplasia Society-2019 revision revealed limb hypoplasia-reduction defects group (39) as the leading one, 24.5%, then followed by FGFR3 chondrodysplasias, osteogenesis imperfecta, and decreased mineralization and polydactyly-syndactyly-triphalangism groups 13.6, 11.1, and 8.9%, respectively. The inheritance pattern was autosomal recessive in 54% and autosomal dominant in 42.6% of index cases. The overall consanguinity rate of the cohort was 33%. The high prevalence of ultrarare diseases along with two or more unrelated autosomal recessive entities running in the same family was noteworthy. This study highlights the pivotal role of postmortem evaluation by an experienced clinical geneticist to achieve a high diagnostic yield in fetal skeletal dysplasia cohorts. The cohort is not only a representation of the spectrum of skeletal dysplasias in a population with a high consanguinity rate but also provides an ideal research group to work on to identify the unknowns of early fetal life.
ALX4 related parietal foramina mimicking encephalocele in prenatal period
(Wiley-Blackwell, 2016) Kayserili, Hülya; Sivrikoz, Tuğba Saraç; Altunoğlu, Umut; Kalelioğlu, İbrahim Halil; Yüksel, Atıl; UyGüner, Oya Zehra; Has, Recep; School of Medicine; Yes; SCHOOL OF MEDICINE
What's Already Known About This Topic? PFM is an autosomal dominantly inherited genetic condition, caused by mutations in ALX4 and MSX2 genes. Reports on prenatally diagnosed cases are rare, and encephalocele remains the most leading differential diagnosis. What Does This Study Add? The full clinical spectrum of autosomal dominant ALX4-related PFM in affected family members can be demonstrated through identification of a prenatal case, by close collaboration of perinatologists and clinical geneticists, as in the four generation family reported herein. © 2016 John Wiley & Sons, Ltd.
Revisiting TOP2B-related phenotypes: three new cases and literature review
(Wiley, 2023) Çepni, Ece; Börklü Yücel, Esra; Avcı, Şahin; Eraslan, Serpil; Kayserili, Hülya; Kalayci, Tugba; KUH (Koç University Hospital); Graduate School of Health Sciences; School of Medicine; Yes; GRADUATE SCHOOL OF HEALTH SCIENCES; KUH (KOÇ UNIVERSITY HOSPITAL); SCHOOL OF MEDICINE
DNA Topoisomerase II beta (TOP2B) acts on DNA topology during transcription and has a critical role in neural development. Heterozygous pathogenic changes in its encoding gene, TOP2B (MIM *126431), has been linked with three overlapping phenotypes characterized by immunodeficiency, acral and urogenital anomalies: Hoffman, BILU and Ablepharon-macrostomia-like syndrome. We herein report on a mother and two sons with distinct TOP2B-phenotype. Two males reported further delineated genital phenotype of males and all reported patients were reviewed for genotypephenotype correlation. We believe the patients reported herein along with the previously defined 11 represent a phenotypic spectrum from mild-to-severe immunological, acral and urogenital involvement, for which we propose the acronym "TOP2B-related Immunodeficiency and Congenital Anomalies Spectrum (TICAS)".
Mutations in CDK5RAP2 cause Seckel syndrome
(Wiley, 2015) Kayserili, Hülya; Yiğit, G.; Brown, K. E.; Pohl, E.; Caliebe, A.; Zahnleiter, D.; Rosser, E.; Bögershausen, N.; Uyguner, Z. O.; Altunoğlu, U.; Nürnberg, G.; Nürnberg, P.; Rauch, A.; Li, Y.; Thiel, C. T.; Wollnik, B.; School of Medicine; Yes; SCHOOL OF MEDICINE
Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.
