Identification of molecular causes of human growth retardation in patients with features of Silver-Russell syndrome

• Applicant: Professor Thomas Eggermann, Ph.D.
• Subject Area: Human Genetics
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 350540879

Silver-Russell syndrome (SRS) belongs to the group of rare diseases, but due to its clinical heterogeneity it is often considered as differential diagnosis in patients with growth retardation. Vice versa, there is a growing number of reports on patients with the clinical diagnosis of SRS, but with molecular disturbances associated with other growth retardation disorders. These molecular and clinical overlaps between SRS and other congenital diseases provide evidence for a functional interaction of the involved molecular factors. However, they make the identification of the basic molecular alterations in SRS and related disorders more and more difficult.SRS is one of the congenital imprinting disorders. These diseases are characterized by similar (epi)genetic disturbances and overlapping clinical features. Several studies, including those of the applicant, indicate that the imprinted region on chromosomes 7 and 11p15.5 contribute to the etiology of the disorder. However, also further chromosomal regions are involved in the pathoetiology of SRS. Systematic studies aiming on these regions are rare and target only copy number variations. With whole exome sequencing (WES), the systematic, comprehensive and genomewide mutation analysis in idiopathic SRS patients is possible now. As the method and the expertise for WES is available at the Institute of Human Genetics in Aachen, and the group of the applicant overviews a large and unique cohort of patients, they intend to perform WES in a cohort of idiopathic SRS families. By (inter)national cooperations and networks, the study cohort can be enlarged, and functional characterizations of mutations is possible if needed.In the proposed project, patients clinically diagnosed as SRS but without one of common (epi)genetic disturbances will be analysed by WES to identify genetic factors contributing to the SRS phenotype. As a result, the spectrum of mutations will be enlarged, and particularly the pathomechanisms will be enlightened. It can be expected that further insights in functional interactions and networks will be achieved, as already shown for some of the (epi)mutations detected in SRS (e.g. IGF axis, imprinted genes network IGN). Up to now, SRS patients without a molecular confirmation of their clinical diagnosis undergo an odyssey of diagnostics and treatment. In fact, some of the treatments can be insufficient or contraindicated, depending on the molecular cause of the disease. Therefore, a further aim of the project is the improvement of the already existing diagnostic algorithm, also by considering the use of molecular tests in newborn born small for gestational age and SRS related features. This early diagnosis will support the differential diagnostics and will contribute to a more directed therapy.

• DFG Programme: Research Grants