Premature Ovarian Failure 10
A number sign (#) is used with this entry because of evidence that premature ovarian failure-10 (POF10) is caused by homozygous mutation in the MCM8 gene (608187) on chromosome 20p.
DescriptionPremature ovarian failure-10 (POF10) represents a syndrome characterized by primary amenorrhea, hypergonadotropic ovarian insufficiency, and genomic instability in somatic cells.
For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).
For a discussion of genetic heterogeneity of age at natural menopause, see MENOQ1 (300488).
Clinical FeaturesAlAsiri et al. (2015) studied 3 sisters from a consanguineous Saudi Arabian family who had premature ovarian failure. All 3 sisters had a normal 46,XX karyotype, elevated follicle-stimulating hormone (FSH; see 136530) levels, and infantile uteri and small atrophic ovaries on pelvic ultrasound. Secondary sexual characteristics were delayed. All 3 patients were also diagnosed with hypothyroidism, which responded to thyroxine.
Tenenbaum-Rakover et al. (2015) reported 2 unrelated consanguineous Arab families with gonadal failure. In the first family, the proband was a 46,XX woman who at age 15 years was completely prepubertal with elevated gonatotropins and primary amenorrhea. At age 22, she had normal pubic hair but only breast bud formation while on hormone replacement therapy. Ultrasound revealed a 6-mm uterus but did not detect ovaries; these findings were confirmed by MRI, which also showed a rudimentary vagina. Her 21-year-old 46,XY brother, who had been diagnosed with a 22q11 microdeletion (DiGeorge syndrome; 188400), exhibited normal pubic hair and penile development, but testicular volume was only 3 mL and he was azoospermic with high basal and GnRH-stimulated gonadotropins, consistent with primary testicular failure. Their father reported delayed puberty and at age 49, had elevated FSH with normal luteinizing hormone (LH; see 152780) and testosterone concentrations. Their mother had delayed menarche at age 15 years, but had regular menses since then and a normal hormonal profile at age 40 years. Other features present in the proband included mild unilateral conductive hearing loss, agenesis of the left kidney, and temporal seizures; both sibs exhibited mild mental retardation. Tenenbaum-Rakover et al. (2015) suggested that these additional features might be related to the familial consanguinity. In the second family, 3 sisters presented consecutively at 14.5 to 15 years of age with delayed puberty, primary amenorrhea, and hypergonadotropic hypogonadism; absence of ovaries and a small uterus were demonstrated by ultrasound and MRI. Their karyotype was 46,XX, and SRY (480000) testing was negative. The sisters responded well to estrogen and progesterone replacement therapy, achieving normal height and pubertal development and experiencing regular menses. Their parents and a healthy older sister had normal pubertal development and normal hormonal profile. Following the sisters' diagnosis, 2 paternal female cousins, aged 30 and 28 years, were also diagnosed with primary hypergonadotropic hypogonadism. There was no history of malignancies in either family.
MappingPremature Ovarian Failure 10
By SNP analysis in a consanguineous Saudi Arabian family in which 3 sisters had hypergonadotropic primary amenorrhea, AlAsiri et al. (2015) identified a 3.3-Mb region of homozygosity on chromosome 20p13-p12.3, flanked by SNPs rs1547618 and rs1012891, which was present only in the affected sibs.
Age At Natural Menopause Quantitative Trait Locus 3
Stolk et al. (2009) conducted a 2-stage genomewide association study for age at natural menopause in 2,979 European women and identified a SNP on chromosome 20p12.3 that was significant: rs236114 (p = 9.71 x 10(-11)). The authors subsequently conducted fine mapping using metaanalysis of imputed data from the stage 1 study and found an additional SNP with higher significance compared to that of the initially reported SNP, located in the same LD block on chromosome 20 as the genomewide-significant SNP (rs16991615; p = 3.00 x 10(-7)). Stolk et al. (2009) noted that rs236114 is located in an intron of the MCM8 gene (608187) and that rs16991615 is a nonsynonymous SNP (E341K) located in exon 9 of MCM8.
In a genomewide association study of 17,438 women, He et al. (2009) found significant association with age at natural menopause for rs16991615 (p = 1.2 x 10(-21)).
Molecular GeneticsBy whole-exome sequencing in a consanguineous Saudi Arabian family in which 3 sisters had hypergonadotropic primary amenorrhea mapping to chromosome 20p13-p12.3, AlAsiri et al. (2015) identified homozygosity for a missense mutation in the MCM8 gene (P149R; 608187.0001) that segregated with the disorder. The mutation was not found in 200 fertile women or in the Exome Variant Server or 1000 Genomes Project databases.
By whole-exome sequencing in 2 unrelated consanguineous Arab families with primary gonadal failure, Tenenbaum-Rakover et al. (2015) identified homozygosity for mutations in the MCM8 gene: a splice site mutation in the first family (608187.0002) and a 2-bp insertion in the MCM8 gene (608187.0003) in the second. Each mutation segregated with disease in the respective family and neither was found in 100 ethnically matched controls.