Expanding the mutation spectrum in FSHD and ICF syndrome

Boogaard, T.L. van den (2018)

Doctoral Thesis

In this thesis two diseases that share a common feature of hypomethylation of repetitive DNA are studied: facioscapulohumeral muscular dystrophy (FSHD) and immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. In FSHD there is hypomethylation of the macrosatellite repeat D4Z4 and the associated DUX4 gene, which is caused by a repeat contraction and/or variants in chromatin modifiers essential for a repressive D4Z4 chromatin structure in somatic cells. In ICF there is hypomethylation of centromeric repeats, which is caused by recessive variants in one of four ICF genes, of which two are established chromatin modifiers. In this thesis, the mutation spectrum of FSHD and ICF has been expanded. The SMCHD1 mutation spectrum in FSHD2 has been expanded with the discovery of exonic SMCHD1 variants, intronic SMCHD1 variants, and whole SMCHD1 gene deletions. In addition, we identified heterozygous variants in a new FSHD2 gene, DNMT3B, in two FSHD2 families. For ICF syndrome we expanded the mutation spectrum in the two most common ICF genes, DNMT3B and ZBTB24.

• FSHD
• ICF
• SMCHD1
• DNMT3B
• ZBTB24
• DUX4
• D4Z4
• Epigenetics
• Chromatin
• Repeats

• All authors: Boogaard, T.L. van den
• Supervisor: Maarel, S.M. van der
• Co-supervisor: Lemmers, R.J.L.F.; Balog, J.
• Committee: Baas, F.; Wijmenga, T.N.; Bokhoven, J.H.L.M. van
• Qualification: Doctor (dr.)
• Awarding Institution: Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-02-13
• ISBN (print): 9789462998278