My research focuses on the identification and characterization of genes and their genetic mechanisms involved in the causation and pathology of neurodevelopmental disorders including autism spectrum disorder. To study the disease specific mechanisms and test potential therapeutic approaches, I use cutting-edge technologies such as patient-derived induced pluripotent stem cell (iPSC) lines and CRISPR/Cas9-based gene editing followed by differentiating to 3-dimensional culture that resembles human brain tissue.
Individuals with ASD have increased risks of developing several other health complications, including various cardiovascular problems. Recent studies highlighted that genes already implicated in autism were also associated with congenital heart diseases, which suggests that some genes may have dual roles in regulating the development of the brain and the heart. Therefore, I also focus on the expression and function of candidate gene(s) with a role in converging pathways in brain and heart development by using the patient derived iPS cells and subsequently differentiating them to brain organoids and cardiomyocytes.
- Made significant contributions to the understanding of genetic mechanism of autism; was a co-author of the first report on exome sequencing and copy number variation analysis in ASD cases and their phenotypically discordant
- Cloned the first gene demonstrating dominant Mendelian inheritance of a Tourette syndrome phenotype. This work, published in the New England Journal of Medicine, pointed for the first time to the involvement of histaminergic neurotransmission in the generation or modulation of tics.
- Identified a novel DIAPH1 gene, expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division, responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature in a multiply-affected consanguineous family.
Adife Gulhan Ercan-Sencicek
Instructor, Masonic Medical Research Institute
After earning my Ph.D. degree in Akdeniz University in 2000 where I studied the genetic diversity in Turkish sesame (Sesamum indicum L.) populations, I completed a second Master’s degree in Cellular and Molecular Biology at University of New Haven 2004 working on finding the early markers in breast cancer. I started my postdoctoral training in the Yale University, Department of Genetics and Child Study Center in Dr. Matthew State’s laboratory where I worked on the identification and characterization of genes and genetic mechanisms involved in neurodevelopmental disorders, including autism, intellectual disability, and Tourette syndrome. During my postdoctoral fellowship, I have learned a great deal about how researchers approach the genetics of complex disorders. I have initiated and participated in several projects, including the study of consanguineous and/or multiply affected families ascertained for autism spectrum disorder (ASD), Tourette syndrome, intellectual disability (ID). After completing the postdoctoral training, I stayed in Dr. State’s lab as an Associate Research Scientist. Later, I was offered a great opportunity to work with Dr. Murat Gunel in the Neurosurgery at Yale school of Medicine where I led the project on whole exome sequencing of consanguineous families from Egypt and Turkey to identify genetic variant conferring autism risk and evaluate the overlap in risk loci for inbred versus outbred autism spectrum disorder populations. I also established the zebrafish animal modeling in the Gunel lab for functional evaluation of strong candidate genes involved in the pathophysiology of intracranial aneurysm. Since September 2018, I have been working as an instructor in Dr. Maria Kontaridis’s lab in the Masonic Medical Research Institute. I plan to use my skills in human genetics to continue gene discovery efforts and analyze the functional consequences of the mutations I discover. My long term plan is to master the skills that will help me to understand the expression and function of candidate gene(s) with a role in converging pathways in brain and heart development by using the patient derived induced pluripotent stem cells which will help us to develop therapeutics. Then, I aim to fully characterize patient mutations through in vivo studies. Despite being primarily in research, I value communicating with the students, sharing my knowledge and experience, and learning from the fresh perspectives that newcomers bring. Therefore, I have also been teaching in Utica College's Biology Department as an adjunct since September, 2018.
Honors and Prizes:
Top ten scientific breakthroughs of the year - Science Magazine
SLITRK1 first reported gene that is associated with Tourette syndrome.
Key Accomplishments and breakthroughs - 20 key discoveries, advances and developments in Tourette and Tic Disorders
Tourette Association in America
HDC is the first gene that identified a link between histaminergic neurotransmission and tics in humans
Completed Research Support
Identifying the genes responsible for ASD and/or ID using multiplex families
NCATS NIH UL1 TR000142 & KL2 TR000140
Yale Center for Clinical Investigation (YCCI) Junior Faculty Scholar (PI: Robert Sherwin)
The goal of this study is to find susceptibility genes in individuals with autism spectrum disorder (ASD) and intellectual disability (ID) by studying families in which the disorder is transmitted in a Mendelian fashion
Molecular Genetic Pathogenesis of Intracranial Aneurysms
The Goal of this study was identification and functional verification of variants associated with Intracranial aneurysm to demonstrate their biological effects.
Disease Gene Discovery in Structural Brain disorders
The major goal is to identify the molecular and genetic basis of structural brain malformations
Integrating the genomics of Autism Spectrum Disorders (ASD) in consanguineous and "idiopathic" families
Key Personal (PI: Murat Gunel)
The goal of the study is to identify novel, rare genetic variants in ASD by employing homozygosity mapping and whole exome sequencing and further evaluate the overlap risk loci for inbred versus outbred ASD populations.
- Cali, E, Suri, M, Scala, M, Ferla, MP, Alavi, S, Faqeih, EA et al.. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities. Genet Med. 2023;25 (1):135-142. doi: 10.1016/j.gim.2022.09.016. PubMed PMID:36399134 .
- Tüysüz, B, Ercan-Sençicek, AG, Özer, E, Göç, N, Yalçınkaya, C, Bilguvar, K et al.. Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM. Turk Arch Pediatr. 2022;57 (5):521-525. doi: 10.5152/TurkArchPediatr.2022.22070. PubMed PMID:35950747 PubMed Central PMC9524456.
- Dong, W, Kaymakcalan, H, Jin, SC, Diab, NS, Tanıdır, C, Yalcin, ASY et al.. Mutation spectrum of congenital heart disease in a consanguineous Turkish population. Mol Genet Genomic Med. 2022;10 (6):e1944. doi: 10.1002/mgg3.1944. PubMed PMID:35481623 PubMed Central PMC9184665.
- Kaymakçalan, H, Ercan-Şençiçek, AG, Cebeci, AN, Dong, W, Yalım Yalçın, AS. A rare etiology of tetralogy of Fallot with pulmonary atresia: Renpenning syndrome. Anatol J Cardiol. 2022;26 (2):149-150. doi: 10.5152/AnatolJCardiol.2021.554. PubMed PMID:35190366 PubMed Central PMC8878915.
- Barak, T, Ristori, E, Ercan-Sencicek, AG, Miyagishima, DF, Nelson-Williams, C, Dong, W et al.. PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans. Nat Med. 2021;27 (12):2165-2175. doi: 10.1038/s41591-021-01572-7. PubMed PMID:34887573 PubMed Central PMC8768030.
- Kaymakcalan, H, Kaya, İ, Cevher Binici, N, Nikerel, E, Özbaran, B, Görkem Aksoy, M et al.. Prevalence and clinical/molecular characteristics of PTEN mutations in Turkish children with autism spectrum disorders and macrocephaly. Mol Genet Genomic Med. 2021;9 (8):e1739. doi: 10.1002/mgg3.1739. PubMed PMID:34268892 PubMed Central PMC8404225.
- Gao, Y, Sun, Y, Ercan-Sencicek, AG, King, JS, Akerberg, BN, Ma, Q et al.. YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes. Int J Mol Sci. 2021;22 (13):. doi: 10.3390/ijms22136649. PubMed PMID:34206257 PubMed Central PMC8268263.
- Hoang, P, Kowalczewski, A, Sun, S, Winston, TS, Archilla, AM, Lemus, SM et al.. Engineering spatial-organized cardiac organoids for developmental toxicity testing. Stem Cell Reports. 2021;16 (5):1228-1244. doi: 10.1016/j.stemcr.2021.03.013. PubMed PMID:33891865 PubMed Central PMC8185451.
- Negron, SG, Ercan-Sencicek, AG, Freed, J, Walters, M, Lin, Z. Both proliferation and lipogenesis of brown adipocytes contribute to postnatal brown adipose tissue growth in mice. Sci Rep. 2020;10 (1):20335. doi: 10.1038/s41598-020-77362-x. PubMed PMID:33230135 PubMed Central PMC7683731.
- Meriç, R, Ercan-Sencicek, AG, Uludağ Alkaya, D, Şahin, Y, Sar, M, Bilguvar, K et al.. A patient with mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratodermia syndrome caused by AP1B1 gene variant. Clin Dysmorphol. 2021;30 (1):54-57. doi: 10.1097/MCD.0000000000000350. PubMed PMID:32969855 .
- Perenthaler, E, Nikoncuk, A, Yousefi, S, Berdowski, WM, Alsagob, M, Capo, I et al.. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases. Acta Neuropathol. 2020;139 (3):415-442. doi: 10.1007/s00401-019-02109-6. PubMed PMID:31820119 PubMed Central PMC7035241.
- Kaymakcalan, H, Yarman, Y, Goc, N, Toy, F, Meral, C, Ercan-Sencicek, AG et al.. Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia. Am J Med Genet A. 2018;176 (2):421-425. doi: 10.1002/ajmg.a.38558. PubMed PMID:29226631 .
- Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol Autism. 2017;8 :21. doi: 10.1186/s13229-017-0137-9. PubMed PMID:28540026 PubMed Central PMC5441062.
- Weiner, DJ, Wigdor, EM, Ripke, S, Walters, RK, Kosmicki, JA, Grove, J et al.. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat Genet. 2017;49 (7):978-985. doi: 10.1038/ng.3863. PubMed PMID:28504703 PubMed Central PMC5552240.
- Gupta, AR, Westphal, A, Yang, DYJ, Sullivan, CAW, Eilbott, J, Zaidi, S et al.. Neurogenetic analysis of childhood disintegrative disorder. Mol Autism. 2017;8 :19. doi: 10.1186/s13229-017-0133-0. PubMed PMID:28392909 PubMed Central PMC5379515.
- Clark, VE, Harmancı, AS, Bai, H, Youngblood, MW, Lee, TI, Baranoski, JF et al.. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48 (10):1253-9. doi: 10.1038/ng.3651. PubMed PMID:27548314 PubMed Central PMC5114141.
- Li, H, Bielas, SL, Zaki, MS, Ismail, S, Farfara, D, Um, K et al.. Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly. Am J Hum Genet. 2016;99 (2):501-10. doi: 10.1016/j.ajhg.2016.07.004. PubMed PMID:27453578 PubMed Central PMC4974110.
- Tüysüz, B, Ercan-Sencicek, AG, Canpolat, N, Koparır, A, Yılmaz, S, Kılıçaslan, I et al.. Renal involvement in patients with mucolipidosis IIIalpha/beta: Causal relation or co-occurrence?. Am J Med Genet A. 2016;170A (5):1187-95. doi: 10.1002/ajmg.a.37543. PubMed PMID:26749367 .
- Bai, H, Harmancı, AS, Erson-Omay, EZ, Li, J, Coşkun, S, Simon, M et al.. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nat Genet. 2016;48 (1):59-66. doi: 10.1038/ng.3457. PubMed PMID:26618343 PubMed Central PMC4829945.
- Sanders, SJ, He, X, Willsey, AJ, Ercan-Sencicek, AG, Samocha, KE, Cicek, AE et al.. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 2015;87 (6):1215-1233. doi: 10.1016/j.neuron.2015.09.016. PubMed PMID:26402605 PubMed Central PMC4624267.
- Dong, S, Walker, MF, Carriero, NJ, DiCola, M, Willsey, AJ, Ye, AY et al.. De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Rep. 2014;9 (1):16-23. doi: 10.1016/j.celrep.2014.08.068. PubMed PMID:25284784 PubMed Central PMC4194132.
- Gupta, AR, Pirruccello, M, Cheng, F, Kang, HJ, Fernandez, TV, Baskin, JM et al.. Rare deleterious mutations of the gene EFR3A in autism spectrum disorders. Mol Autism. 2014;5 :31. doi: 10.1186/2040-2392-5-31. PubMed PMID:24860643 PubMed Central PMC4032628.
- Ercan-Sencicek, AG, Jambi, S, Franjic, D, Nishimura, S, Li, M, El-Fishawy, P et al.. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. Eur J Hum Genet. 2015;23 (2):165-72. doi: 10.1038/ejhg.2014.82. PubMed PMID:24781755 PubMed Central PMC4297910.
- Baldan, LC, Williams, KA, Gallezot, JD, Pogorelov, V, Rapanelli, M, Crowley, M et al.. Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron. 2014;81 (1):77-90. doi: 10.1016/j.neuron.2013.10.052. PubMed PMID:24411733 PubMed Central PMC3894588.
- Willsey, AJ, Sanders, SJ, Li, M, Dong, S, Tebbenkamp, AT, Muhle, RA et al.. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 2013;155 (5):997-1007. doi: 10.1016/j.cell.2013.10.020. PubMed PMID:24267886 PubMed Central PMC3995413.
- Novarino, G, El-Fishawy, P, Kayserili, H, Meguid, NA, Scott, EM, Schroth, J et al.. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012;338 (6105):394-7. doi: 10.1126/science.1224631. PubMed PMID:22956686 PubMed Central PMC3704165.
- Sanders, SJ, Murtha, MT, Gupta, AR, Murdoch, JD, Raubeson, MJ, Willsey, AJ et al.. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485 (7397):237-41. doi: 10.1038/nature10945. PubMed PMID:22495306 PubMed Central PMC3667984.
- Ercan-Sencicek, AG, Davis Wright, NR, Sanders, SJ, Oakman, N, Valdes, L, Bakkaloglu, B et al.. A balanced t(10;15) translocation in a male patient with developmental language disorder. Eur J Med Genet. 2012;55 (2):128-31. doi: 10.1016/j.ejmg.2011.12.005. PubMed PMID:22266071 PubMed Central PMC3322462.
- Fernandez, TV, Sanders, SJ, Yurkiewicz, IR, Ercan-Sencicek, AG, Kim, YS, Fishman, DO et al.. Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry. 2012;71 (5):392-402. doi: 10.1016/j.biopsych.2011.09.034. PubMed PMID:22169095 PubMed Central PMC3282144.
- Celestino-Soper, PB, Shaw, CA, Sanders, SJ, Li, J, Murtha, MT, Ercan-Sencicek, AG et al.. Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE. Hum Mol Genet. 2011;20 (22):4360-70. doi: 10.1093/hmg/ddr363. PubMed PMID:21865298 PubMed Central PMC3196886.
- Sanders, SJ, Ercan-Sencicek, AG, Hus, V, Luo, R, Murtha, MT, Moreno-De-Luca, D et al.. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70 (5):863-85. doi: 10.1016/j.neuron.2011.05.002. PubMed PMID:21658581 PubMed Central PMC3939065.
- Krusong, K, Ercan-Sencicek, AG, Xu, M, Ohtsu, H, Anderson, GM, State, MW et al.. High levels of histidine decarboxylase in the striatum of mice and rats. Neurosci Lett. 2011;495 (2):110-4. doi: 10.1016/j.neulet.2011.03.050. PubMed PMID:21440039 PubMed Central PMC3081964.
- Bayrakli, F, Bilguvar, K, Ceyhan, D, Ercan-Sencicek, AG, Cankaya, T, Bayrakli, S et al.. Heterozygous 5p13.3-13.2 deletion in a patient with type I Chiari malformation and bilateral Duane retraction syndrome. Clin Genet. 2010;77 (5):499-502. doi: 10.1111/j.1399-0004.2010.01411.x. PubMed PMID:20447154 .
- Ercan-Sencicek, AG, Stillman, AA, Ghosh, AK, Bilguvar, K, O'Roak, BJ, Mason, CE et al.. L-histidine decarboxylase and Tourette's syndrome. N Engl J Med. 2010;362 (20):1901-8. doi: 10.1056/NEJMoa0907006. PubMed PMID:20445167 PubMed Central PMC2894694.