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Identification and Characterization of Candidate Genes in Individuals with Autosomal Recessive Intellectual Disability”

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Identification and Characterization of Candidate Genes in Individuals with Autosomal Recessive Intellectual Disability” “Identification and characterization of candidate genes in individuals with autosomal recessive intellectual disability” Identifizierung und Charakterisierung von Kandidatengenen bei Individuen mit autosomal rezessiver mentaler Retardierung Der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. rer. nat. Vorgelegt von Hasan Tawamie aus Edleb, Syrien 1 Als Dissertation genehmigt von der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Tag der mündlichen Prüfung: 26.02.2018 Vorsitzender des Promotionsorgans: Prof. Dr. Georg Kreimer Gutachter: Prof. Dr. André Reis Gutachter: Prof. Dr. Johann Brandstätter 2 Table of Contents 1 Summary 1 2 Zusammenfassung 2 3 Introduction 3 3.1 Intellectual disability; definition, classification 3 3.2 Genetic causes of intellectual disability 3 4 Aim of this thesis and strategies to identify genes for autosomal recessive intellectual disability 6 5 Families; brief clinical description and results of mapping 7 5.1 Families, ethic statement, and available mapping results 7 5.2 Homozygosity mapping 9 6 Methods 12 6.1 DNA Isolation and its quality measurement 12 6.2 Polymerase Chain Reaction (PCR) 13 6.3 Sanger Sequencing 18 6.4 Next Generation Sequencing Technologies 19 6.5 Plasmids cloning 24 6.6 Cell Culture 26 6.7 Protein isolation and concentration measurement 28 6.8 Small interfering RNAs (siRNAs) 29 6.9 Cell proliferation assay 30 6.10 Wound-healing assay 30 6.11 SK-N-BE(2) differentiation assay 30 7 Reagents and Materials 31 7.1 Consumables 31 7.2 Chemicals, Enzymes, Standards 32 7.3 Buffers and Solutions 35 7.4 Vectors 38 7.5 Antibodies 38 7.6 TaqMan Probes 39 7.7 Kits 39 7.8 Appliances 40 7.9 Databases and Softwares 41 I 8 Results 43 8.1 Exome sequencing of nineteen affected individuals with intellectual disability 43 8.2 Pathogenic variants in known genes for intellectual disability 44 8.3 Variants in novel genes 48 9 Discussion 68 9.1 Identification of mutations in known ID genes 68 9.2 Identification of pathogenic variants in novel ID genes 70 9.3 Concluding remarks 77 10 Literaturverzeichnis 82 11 Curriculum vitae of Hasan Tawamie 92 12 List of Publications 93 13 Danksagung 95 14 Erklärung 96 II 1 Summary By applying a combination of homozygosity mapping and whole exome sequencing I aimed in this thesis at identifying the genetic causes of intellectual disability in nineteen consanguineous families with two or more affected children. Following identification of genetic variants I prioritized them based on frequency, computer-based modeling, protein function, and familial segregation. In two families, I identified homozygous pathogenic variants in AHI1 and SPG20 that were already associated with Joubert syndrome and Troyer syndrome, respectively. In 14 families, I identified 15 candidate variants in genes not previously associated with intellectual disability, BDH1, CCAR2, EZR, FAR1, KCTD18, KIAA0586, LRCH3, OGDHL, PGAP1, PGAP2, PUS7, SKIDA1, SVBP, TAF13, and TMTC3. In three families, I could identify no candidate variants. To confirm the pathogenicity of the identified variants, working hypotheses were generated based on the putative variant effect and/or on the protein function and on results of the molecular modeling of the altered protein. For SVBP I could show severe reduction of the secretion of the interaction partner VASH1 in cells with overexpression of the altered SVBP. For TAF13 I could prove that the variant leads to major disruption of the interaction between TAF13 and TAF11. TAF13 is involved in transcription. Thus, I have also performed whole RNA sequencing on TAF13-knocked down neuron-like cell lines. This revealed that transcription of genes that are involved in proliferation and differentiation of neurons is impacted. I proved this in cell cultures. Since further analyses was not possible within this thesis, experiments to prove the pathogenicity and/or causality of the variants in EZR, FAR1, KIAA0586, PGAP1, PGAP2, and TMTC3 were done by cooperation partners, after I have performed preliminary work of validation, segregation, testing for frequency in general population, and vector construction. In conclusion, in this thesis I could identify or contribute to the identification of 8 novel genes for autosomal recessive intellectual disability. 1 2 Zusammenfassung In dieser Arbeit habe ich mittels einer Kombination von Homozygotie-Kartierung und Exom- Sequenzierung 19 konsanguinen Familien mit zwei oder mehr Kindern mit einer mentalen Retardierung (MR) untersucht. Auf der Grundlage der Variantenfrequenz, der Computer- basierten Modellierungsanalyse, der Proteinfunktion und der familiären Segregation priorisierte ich die identifizierten Kandidatenvarianten. In zwei Familien habe ich in den Genen AHI1 und SPG20 jeweils eine pathogene homozygote Variante identifiziert, und somit das Vorliegen des Joubert- bzw. Troyer-Syndroms bewiesen. In 14 Familien identifizierte ich Kandidatenvarianten in 15 Genen, die noch nicht mit mentaler Retardierung verbunden waren; BDH1, CCAR2, EZR, FAR1, KCTD18, KIAA0586, LRCH3, OGDHL, PGAP1, PGAP2, PUS7, SKIDA1, SVBP, TAF13 und TMTC3. In 3 Familien konnte ich keine Kandidatenvarianten identifizieren. Um die Pathogenität der identifizierten Varianten zu bestätigen, habe ich auf Grundlage des putativen Effekts der Varianten, der Proteinfunktionen und der Modellierungsanalysen eine Arbeitshypothese gestellt, welche ich dann mittels funktioneller Analysen verfolgt habe. Für die Variante in SVBP bewies ich, dass das instabile, veränderte SVBP eine schwere Reduktion der Sekretion seines Interaktionsfaktors VASH1 verursacht. Für die Variante in TAF13 habe nachgewiesen, dass die Variante zu einer Störung der Interaktion zwischen TAF13 und TAF11 führt. TAF13 ist in der Transkription involviert. Daher führte ich eine transkriptomweite Sequenzierungsanalyse und konnte zeigen, dass insbesondere die Proliferation und Differenzierung von Neuronen betroffen ist. Dies habe ich dann in Zellkulturen gezeigt. Weil weitere Analysen zur Bestätigung der Pathogenität und/oder Kausalität von weiteren identifizierten Varianten im Rahmen dieser Arbeit nicht möglich waren, wurden diese von Kooperationspartnern für die Gene FAR1, KIAA0586, PGAP1, PGAP2 und TMTC3 absolviert, nachdem ich die Basisanalysen (Validierung, Segregation, Prävalenz in der Allgemeinbevölkerung und Vektorkonstruktion) durchgeführt habe. Zusammengefasst konnte ich in dieser Arbeit zur Identifizierung und Charakterisierung von 8 neuen Genen für die autosomal-rezessive mentale Retardierung beitragen. 2 3 Introduction 3.1 Intellectual disability; definition, classification Intellectual disability (ID) is a condition of arrested or incomplete development of mind characterized by impairment of skills that contribute to the overall level of intelligence, i.e. cognitive, language, motor, and social abilities. ID can occur independently or accompanied with other congenital or/and neurological features such as epilepsy, sensory impairment, and autism spectrum disorders (ASD) (Vissers et al. 2016) . Many studies report that prevalence of ID ranges between 1 and 3 % (Moeschler and Shevell 2014). Also, it was reported that the incidence of ID is inversely correlated with socio- economic standards such as malnutrition, cultural deprivation and inadequate health care. With lifetime costs of 1–2 million US dollars, ID is one of the leading socio-economic challenges of health care in Europe and the United States (Polder et al. 2002). However, ID still receives little public attention, because many health care professionals, organizations and parents do not perceive it as a health condition but rather a social or educational issue (Salvador-Carulla and Bertelli 2008). Classification of ID provides some clarity of ID severity and the level of support that will be required in the educational system and beyond. Based on the degree of mental impairment, ID is classified into; profound (IQ<20), severe (IQ 20–34), moderate (IQ 35–49), and mild ID (IQ 50–69) (Rabe-Jablonska and Bienkiewicz 1994). 3.2 Genetic causes of intellectual disability While many exogenous factors like maternal alcohol abuse during pregnancy, infections, birth complications and extreme malnutrition play a role in the etiology of ID, pathogenic genetic variants seem to be the cause in the majority of the cases, at least in countries with developed health systems (van Bokhoven 2011; Rauch et al. 2012). The widespread introduction of cytogenetic technologies allowed to recognize the chromosomal abnormalities as a common cause of ID in about 15% of cases (van Karnebeek, Michelson et al. 2011) including the numerical abnormalities like in trisomy 21 (Down syndrome). The introduction of genomic microarrays allowed the genome-wide detection of CNVs at finer resolution to rapidly replace G-banded karyotyping as the first-tier test for ID (Miller et al. 2010) and revealed submicroscopic aberrations as disease causing in about 6- 10% of patients with intellectual disability (Willemsen and Kleefstra 2014). For many years, linkage analyses using large families with only male patients led to the identification of several genes on the X chromosome. The heterogeneous group of X-linked 3 intellectual disability disorders (XLID) has now more than 100 genes that explain 5%-10% of ID in males (Lubs et al. 2012). On the other hand, the progress of identifying autosomal recessive intellectual disability (ARID) genes was slow, primarily due to small family size
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