Hum Mol Genet. 2019 Apr 1. pii: ddz066. doi: 10.1093/hmg/ddz066. [Epub ahead of print]
MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration.
Hamanaka K1, Takata A1, Uchiyama Y1,2, Miyatake S1,3, Miyake N1, Mitsuhashi S1, Iwama K1, Fujita A1, Imagawa E1, Alkanaq AN1, Koshimizu E1, Azuma Y1,4, Nakashima M5, Mizuguchi T1, Saitsu H5, Wada Y6, Minami S7, Katoh-Fukui Y8, Masunaga Y9, Fukami M8, Hasegawa T10, Ogata T9, Matsumoto N1.
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Disorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case-control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Müllerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.

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PMID: 30985895 DOI: 10.1093/hmg/ddz066