@article{BahenaDaftarianMaroofianetal.2022,
  author    = {Bahena, Paulina and Daftarian, Narsis and Maroofian, Reza and Linares, Paola and Villalobos, Daniel and Mirrahimi, Mehraban and Rad, Aboulfazl and Doll, Julia and Hofrichter, Michaela A. H. and Koparir, Asuman and R{\"o}der, Tabea and Han, Seungbin and Sabbaghi, Hamideh and Ahmadieh, Hamid and Behboudi, Hassan and Villanueva-Mendoza, Cristina and Cort{\´e}s-Gonzalez, Vianney and Zamora-Ortiz, Rocio and Kohl, Susanne and Kuehlewein, Laura and Darvish, Hossein and Alehabib, Elham and La Arenas-Sordo, Maria de Luz and Suri, Fatemeh and Vona, Barbara and Haaf, Thomas},
  title     = {Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment},
  series = {Human Genetics},
  volume    = {141},
  journal   = {Human Genetics},
  number    = {3-4},
  issn      = {1432-1203},
  doi       = {10.1007/s00439-021-02303-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267750},
  pages     = {785-803},
  year      = {2022},
  abstract  = {Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf-blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75\%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15\%) probands displayed other genetic entities with dual sensory impairment, including Alstr{\"o}m syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf-blind cohort was 92\%. Two (3\%) probands were partially solved and only 3 (5\%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.},
  language  = {en}
}
@article{DollKolbSchnappetal.2020,
  author    = {Doll, Julia and Kolb, Susanne and Schnapp, Linda and Rad, Aboulfazl and R{\"u}schendorf, Franz and Khan, Imran and Adli, Abolfazl and Hasanzadeh, Atefeh and Liedtke, Daniel and Knaup, Sabine and Hofrichter, Michaela AH and M{\"u}ller, Tobias and Dittrich, Marcus and Kong, Il-Keun and Kim, Hyung-Goo and Haaf, Thomas and Vona, Barbara},
  title     = {Novel loss-of-function variants in CDC14A are associated with recessive sensorineural hearing loss in Iranian and Pakistani patients},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {1},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21010311},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285142},
  year      = {2020},
  abstract  = {CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.},
  language  = {en}
}
@article{HofrichterMojaradDolletal.2018,
  author    = {Hofrichter, Michaela A. H. and Mojarad, Majid and Doll, Julia and Grimm, Clemens and Eslahi, Atiye and Hosseini, Neda Sadat and Rajati, Mohsen and M{\"u}ller, Tobias and Dittrich, Marcus and Maroofian, Reza and Haaf, Thomas and Vona, Barbara},
  title     = {The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family},
  series = {BMC Medical Genetics},
  volume    = {19},
  journal   = {BMC Medical Genetics},
  number    = {81},
  doi       = {10.1186/s12881-018-0598-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175755},
  year      = {2018},
  abstract  = {Background: Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family. Methods: Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed. Results: The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change. Conclusion: In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.},
  language  = {en}
}
@article{DollVonaSchnappetal.2020,
  author    = {Doll, Julia and Vona, Barbara and Schnapp, Linda and R{\"u}schendorf, Franz and Khan, Imran and Khan, Saadullah and Muhammad, Noor and Alam Khan, Sher and Nawaz, Hamed and Khan, Ajmal and Ahmad, Naseer and Kolb, Susanne M. and K{\"u}hlewein, Laura and Labonne, Jonathan D. J. and Layman, Lawrence C. and Hofrichter, Michaela A. H. and R{\"o}der, Tabea and Dittrich, Marcus and M{\"u}ller, Tobias and Graves, Tyler D. and Kong, Il-Keun and Nanda, Indrajit and Kim, Hyung-Goo and Haaf, Thomas},
  title     = {Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families},
  series = {Genes},
  volume    = {11},
  journal   = {Genes},
  number    = {11},
  issn      = {2073-4425},
  doi       = {10.3390/genes11111329},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219293},
  year      = {2020},
  abstract  = {The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9\%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4\%). Overall, seven missense variants (53.8\%), three nonsense variants (23.1\%), two frameshift variants (15.4\%), and one splice-site variant (7.7\%) were observed. Syndromic HL was identified in five (23.8\%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.},
  language  = {en}
}
@phdthesis{Doll2024,
  author    = {Doll, Julia},
  title     = {Identifizierung und Charakterisierung neuer, mit H{\"o}rst{\"o}rungen assoziierter Gene und Varianten mittels Exom-Sequenzierung},
  doi       = {10.25972/OPUS-26109},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261097},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Laut des aktuellen Reports der Weltgesundheitsorganisation sind ca. 466 Millionen Menschen weltweit von einer H{\"o}rst{\"o}rung (HS) betroffen. Durch die enorme Heterogenit{\"a}t und die klinische Variabilit{\"a}t, die diese Erkrankung ausmacht, und viele bisher nicht mit HS assoziierte Gene, bleibt ein großer Teil der erblich bedingten HS in vielen Familien unaufgekl{\"a}rt. Die Entwicklung moderner Techniken, wie die Next-Generation Sequenzierung (NGS) und der Fortschritt bei der Untersuchung von Modellorganismen trugen jedoch in den letzten Jahren immens dazu bei, neue Gene zu identifizieren, die innerhalb des auditorischen Signalwegs oder damit assoziierten Strukturen beteiligt sind. Die vorliegende Arbeit umfasst Ergebnisse dreier Ver{\"o}ffentlichungen, in denen iranische und pakistanische Familien und eine deutsche Familie mit erblich bedingter HS untersucht und neue, krankheitsverursachende Varianten identifiziert und funktionell charakterisiert wurden. Im ersten Abschnitt konnten zwei neue rezessive Varianten im CDC14A-Gen als krankheitsverursachend identifiziert werden, die zu einem potentiellen Funktionsverlust des kodierten Proteins in einer iranischen und einer pakistanischen Familie f{\"u}hren. Mit Hilfe einer funktionellen Charakterisierung auf RNA-Ebene (Spleiß-Assay und RT-qPCR) konnte der Funktionsverlust beider Varianten best{\"a}tigt werden. Der zweite Abschnitt umfasst eine deutsche Familie mit sieben von einer HS betroffenen Familienmitgliedern, in der eine heterozygote missense Variante in MYO3A identifiziert wurde. In der vorliegenden Arbeit konnte somit die erste autosomal dominante Variante in einer europ{\"a}ischen Familie mit einer bilingualen, sensorineuralen Hochtonschwerh{\"o}rigkeit beschrieben werden und der dominante Charakter von MYO3A best{\"a}tigt werden. Im dritten Abschnitt konnten die krankheitsverursachenden Varianten in 13 Familien aus einer Kohorte mit 21 pakistanischen Familien mit einer syndromalen und nicht-syndromalen HS ausfindig gemacht werden. Hierbei wurden sowohl bekannte, als auch bisher nicht beschriebene Varianten detektiert. Die Aufkl{\"a}rungsrate innerhalb dieser Kohorte betrug 61,9\% und es konnte somit das Spektrum syndromaler und nicht-syndromaler HS erweitert werden. Der letzte Abschnitt dieser Arbeit beschreibt eine iranische Familie mit einer milden HS und milden Intelligenzminderung, in der eine homozygote missense Variante im Kandidatengen DBN1 ausfindig gemacht wurde. Um die Funktion und die Auswirkungen eines potentiellen Verlusts des codierten Proteins Drebrin zu untersuchen, wurden immunhistochemische F{\"a}rbungen und auditorische Messungen an Dbn1 Knockout (KO)-M{\"a}usen durchgef{\"u}hrt. Hierbei konnte eine Expression innerhalb der Nervenfasern, die innere Haarzellen innervieren, nachgewiesen werden. Eine leicht verl{\"a}ngerte Latenz f{\"u}r die ABR-Welle IV in KO-M{\"a}usen im Vergleich zum Wildtyp ergab den Hinweis auf einen Defekt innerhalb des zentralen auditorischen Signalwegs, der m{\"o}glicherweise mit einer Sprachverarbeitungsst{\"o}rung im Menschen korreliert.},
  subject      = {H{\"o}rst{\"o}rung},
  language  = {de}
}