Molekulargenetische Charakterisierung syndromaler, genetischer Erkrankungen mittels Next-Generation-Sequencing
by Tabea Rebecca Ochmann née Beyer
Date of Examination:2025-04-15
Date of issue:2025-04-03
Advisor:Prof. Dr. Bernd Wollnik
Referee:Prof. Dr. Bernd Wollnik
Referee:Prof. Dr. Knut Brockmann
Persistent Address:
http://dx.doi.org/10.53846/goediss-11181
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Abstract
English
Rare diseases form a heterogeneous group of diseases that encompass a broad clinical spec-trum with a large variety of clinical features and characteristics. In the European Union, a disease is considered rare if it affects fewer than 1 in 2,000 people. This definition currently covers around 8,000 different diseases. Although each separate disease only affects a few people, a total of around 4 million people in Germany and around 30 million people in the European Union are affected by a rare disease. It is currently estimated that around 70-80% of rare diseases have a genetic cause. The identification of a causal genetic alteration leading to these diseases is therefore of great importance both with regard to possible therapy op-tions and for genetic counselling of affected patients and families. In recent years, the devel-opment and establishment of new methods using next-generation sequencing-based analysis strategies has contributed to the identification of a large number of new genes and alterations causative for rare diseases. Thus, NGS had a major impact on both human genetic research and routine diagnostic analyses. In this study, a cohort of ten patients was genetically characterized using NGS-based meth-ods with the aim of identifying causal genetic alterations for the diseases in question. The Zusammenfassung 112 molecular genetic examination of this patient cohort was initially carried out using mende-liom sequencing and subsequently continued by exome analysis if mendeliom sequencing did not lead to the identification of a causative alteration. Using this strategy, I was able to able to identify variants in three cases that were assessed as causative/possible causative via men-deliom sequencing. In one patient with developmental delay and facial abnormalities, I was able to diagnose Coffin-Siris syndrome by identifying a pathogenic alteration, c.4182delT; p.Y1407*fs, in the ARID1B gene. In a second patient, a homozygous, pathogenic alteration in the LRP4 gene was identified during mendeliom sequencing, which confirmed the suspected diagnosis of Cenani-Lenz syndactyly syndrome in this patient. For cases that had not been conclusively resolved by mendeliom sequencing and two additional cases, exome sequencing was subse-quently carried out, which led to the identification of the causative genetic alteration in the WNT1 (c.774C>A) and CDK10 (c.608+1G>A) genes in two patients and genetically con-firmed the suspected diagnoses of osteogenesis imperfecta and Al Kaissi syndrome. In addi-tion, in two cases I was able to identify variants in candidate genes, but whose causality could not yet be conclusively clarified. In summary, I was able to show in the context of the present work that NGS-based human genetic testing methods are of outstanding importance both in patients with specific sus-pected diagnoses, such as cases with suspected Kabuki, Cenani-Lenz syndactyly or Coffin-Siris syndrome, and especially in patients with unclear, inconclusive suspected diagnoses and missing clinical assignments. The human genetic confirmation or detection of a specific di-agnosis is very important for both the patient and the healthcare professionals. After molec-ular genetic diagnosis, statements can be made about the risk of recurrence, which can have a decisive impact on family planning. The (patho)physiology can thus be better understood and a needs-based therapy is possible, which in some cases can be started before the onset of symptoms.
Keywords: genetics; NGS
