Molecular investigation of Beckwith-Wiedemann syndrome and Silver-Russell Syndrome

Lan-Leung, Benoît (2018). Molecular investigation of Beckwith-Wiedemann syndrome and Silver-Russell Syndrome. University of Birmingham. Ph.D.

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Abstract

The investigation of human imprinting disorders has provided important insights into the role of genomic imprinting in normal health and development. Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder associated with abnormal function of 11p15.5 imprinted genes that’s result, most commonly, from the epimutation (loss of maternal allele methylation) at the imprinting centre KCNQ1OT1:TSS-DMR (BWS_IC2). In contrast, Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth retardation and, most commonly, epimutations (loss of paternal allele methylation) at H19/IGF2:IG-DMR. Using Infinium 450K methylation array, I performed methylation profiling at 46 imprinted differentially methylated regions in 90 BWS and 21 SRS patients. I report epimutations at other imprinting centres outside of chromosome 11p15.5 in 40% of BWS_IC2 but not in SRS_IC1. The investigation of the potential underlying causes of this multilocus methylation disturbances (MLID) epigenotype in BWS_IC2 individuals indicated that several factors might contribute to the BWS phenotype and MLID epigenotype. Although not an universal finding, the use of assisted reproductive technology was significantly associated with MLID in my cohort of BWS_IC2 patients. Furthermore, using whole-exome sequencing strategy, I describe new potential candidate genes for trans-acting factors regulating methylation at imprinting DMRs.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):