Genome Analysis Shows Meiosis Gene Mutation Causes Primary Ovarian Insufficiency

A mutation in a gene linked to the process of meiosis was found in two sisters diagnosed with primary ovarian insufficiency (POI), a syndrome that prevented them from reaching sexual maturity.

Mammals and many other organisms achieve reduction and recombination through a process called meiosis, which is recognizable by the presence of a distinctive structure—the synaptonemal complex (SCS), —that links the chromosomes together and is essential for meiosis to complete. The protein encoded by the SYCE1 gene (synaptonemal complex central element 1) may have a role in the synaptonemal complex assembly, stabilization, and recombination. Genes involved in essential steps in chromosome synapsis and recombinations during meiosis, such as SYCE1, have been shown to cause POI in animal models but not in humans.

Investigators at Tel Aviv University (Israel) worked with two daughters of consanguineous parents (first cousins) from a 13-member Israeli-Arab family who had been diagnosed with POI. Genotyping was performed in the patients, their parents, four unaffected siblings, and a group of 90 ethnically matched control individuals.

DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed, and genotypes of the additional family members and the control subjects were determined by Sanger sequencing.

Results revealed a nonsense homozygous mutation in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects.

"One of my main topics of interest is puberty," said first author Dr. Liat de Vries, professor of medicine at Tel Aviv University. "The clinical presentation of the 2 sisters, out of 11 children of first-degree cousins, was interesting. In each of the girls, POI was expressed differently. One had reached puberty and was almost fully developed but did not have menses. The second, 16 years old, showed no signs of development whatsoever. By identifying the genetic mutation, we saved the family a lot of heartache by presenting evidence that any chance of inducing fertility in these two girls is slight. As bad as the news is, at least they will not spend years on fertility treatments and will instead invest efforts in acquiring an egg donation, for example. Knowledge is half the battle—and now the entire family knows it should undergo genetic testing for this mutation."

The paper was published in the July 25, 2014, online edition of the Journal of Clinical Endocrinology and Metabolism.

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