Ovarian Dysgenesis 4

A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-4 (ODG4) is caused by homozygous mutation in the MCM9 gene (610098) on chromosome 6q22.

For a general phenotypic description and a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).

Clinical Features

Wood-Trageser et al. (2014) described 3 affected individuals from 2 unrelated consanguineous Kurdish families with ovarian dysgenesis. In the first family, 2 sisters had hypergonadotropic primary amenorrhea, short stature, low weight, and a normal 46,XX karyotype. Estradiol levels were low, whereas luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) levels were high. Prolactin (PRL; 176760) levels were normal. Ovaries were not identified on pelvic ultrasound, and uteri were infantile. Both sisters responded to combined estrogen-progestin replacement therapy, achieving regular menses, appropriate bone ages, and Tanner stages of pubic hair and breast development. In the second family, a 16-year-old girl had primary amenorrhea, lack of breast development, short stature, low weight, and a normal 46,XX karyotype. Examination revealed minimal breast development, with Tanner stage III pubic hair and stage II axillary hair development, and a bone age of 11 years. Pelvic ultrasound showed an infantile uterus and no visible ovaries. Basal estradiol level was low, with high LH and FSH and normal PRL levels. Combined estrogen-progestin replacement therapy resulted in regular menses and increased height, weight, and breast development. In both families, unaffected mothers and sisters underwent normal pubertal development.

Fauchereau et al. (2016) reported a consanguineous Arab family in which 2 sisters had primary amenorrhea secondary to hypogonadism, incomplete development of secondary sexual characteristics, delayed bone age, normal adult stature, and normal 46,XX karyotype. One had no uterus or ovaries visible, whereas the other had a uterus and small ovaries. Both had vaginal bleeding after hormonal replacement. Estradiol levels were low, while LH and FSH levels were high. One of the sisters had normal PRL and thyroid hormone levels. The mother had menarche at age 13 and menopause at age 47. Infertility was reported in the mother's family. An unaffected sister was fertile and conceived naturally.

Mapping

By DNA copy number analysis and homozygosity mapping in a consanguineous Kurdish family in which 2 sisters had ovarian dysgenesis, Wood-Trageser et al. (2014) identified 2 contiguous regions of homozygosity on chromosomes 1p34 and 6q21-q33 that were shared by the 2 affected sisters but not by the unaffected family members.

Molecular Genetics

By whole-exome sequencing in a consanguineous Kurdish family in which 2 sisters had ovarian dysgenesis, Wood-Trageser et al. (2014) identified homozygosity for a splice site mutation in the MCM9 gene (610098.0001) on chromosome 6q22. Whole-exome sequencing in a second, unrelated Kurdish family revealed homozygosity for a nonsense mutation in MCM9 (R132X; 610098.0002) in a 16-year-old girl with ovarian dysgenesis. Sanger sequencing confirmed that the mutations segregated with disease in each family; neither mutation was found in 200 fertile women or in the NHLBI Exome Variant Server or 1000 Genomes Project databases.

In 2 sisters in a consanguineous Arab family with primary ovarian insufficiency, Fauchereau et al. (2016) identified homozygosity for a nonsense mutation in the MCM9 gene (E495X; 610098.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not present in the ExAC database.