Ovarian Dysgenesis 6

A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-6 (ODG6) is caused by homozygous mutation in the NUP107 gene (607617) on chromosome 12q15. One such family has been reported.

Description

Ovarian dysgenesis-6 is characterized by absence of spontaneous pubertal development in females with elevated gonadotropin levels, small uterus, and absence of ovarian tissue on imaging studies. Males appear to be unaffected (Weinberg-Shukron et al., 2015).

For a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).

Clinical Features

Weinberg-Shukron et al. (2015) studied a girl from a large consanguineous Palestinian family who presented at age 15 years with absence of spontaneous puberty and had minimal breast development, pubertal hair at Tanner stage II, primary amenorrhea, and elevated luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) levels. Ultrasound and MRI of the pelvis showed a relatively small uterus, and ovaries were not detected. After 24 months of hormone replacement therapy, she had achieved mean familial height, secondary sexual characteristics, and regular menstruation. She had an affected younger sister and 3 affected female cousins, who all presented with absence of spontaneous puberty and elevated gonadotropic hormones, with small uterus and absent ovaries on imaging studies. All men in the family had normal pubertal development, and married men had multiple children.

Inheritance

The transmission pattern of ovarian dysgenesis in the family reported by Weinberg-Shukron et al. (2015) was consistent with autosomal recessive inheritance.

Mapping

In a large Palestinian family in which 5 females had ovarian dysgenesis, Weinberg-Shukron et al. (2015) performed homozygosity mapping and identified 2 large regions of homozygosity, spanning a total of 9.3 Mb, on chromosomes 4 (chr4:152,221,451-157,617,198, GRCh37) and 12 (chr12:68,756,371-72,742,353, GRCh37). There were no obvious functional candidate genes in either region.

Molecular Genetics

In 2 affected cousins from a large Palestinian family with ovarian dysgenesis, Weinberg-Shukron et al. (2015) performed whole-exome sequencing and identified homozygosity for a missense mutation (D447N; 607617.0005) that segregated with disease in the family and was not found in 150 ethnically matched controls. Although male fertility appeared to be normal in the family, there were no homozygotes among the male family members tested.