Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency
L de Vries, DM Behar, P Smirin-Yosef… - The Journal of …, 2014 - academic.oup.com
L de Vries, DM Behar, P Smirin-Yosef, I Lagovsky, S Tzur, L Basel-Vanagaite
The Journal of Clinical Endocrinology & Metabolism, 2014•academic.oup.comContext: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle
dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early
menopause. Genes involved in essential steps in chromosome synapsis and recombination
during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been
shown to cause POI in animal models. We describe for the first time a homozygous mutation
in SYCE1 in humans. Objective: To identify the genetic cause of POI in an Israeli Arab family …
dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early
menopause. Genes involved in essential steps in chromosome synapsis and recombination
during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been
shown to cause POI in animal models. We describe for the first time a homozygous mutation
in SYCE1 in humans. Objective: To identify the genetic cause of POI in an Israeli Arab family …
Context
Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans.
Objective
To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree.
Setting and Design
A family-based genetic study conducted at a tertiary medical center.
Patients
Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI. Genotyping was performed in the index patients, their parents, and four unaffected siblings.
Intervention
DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals.
Results
A nonsense homozygous mutation (c.613C>T) was identified 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.
Conclusions
Given the known function of the SYCE1 gene, we suggest that the nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function.
Oxford University Press