DO: 0080872;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q21.2 | Premature ovarian failure 15 | 618096 | Autosomal recessive | 3 | FANCM | 609644 |
A number sign (#) is used with this entry because of evidence that premature ovarian failure-15 (POF15) is caused by homozygous or compound heterozygous mutation in the FANCM gene (609644) on chromosome 14q21.
Premature ovarian failure-15 (POF15) is characterized by primary amenorrhea, oligomenorrhea, or secondary amenorrhea; small ovaries with reduced or absent follicles; and elevated gonadotropic hormones (Fouquet et al., 2017; Jaillard et al., 2020; Heddar et al., 2022).
For a general phenotypic description and discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).
Fouquet et al. (2017) studied 2 Finnish sisters with premature ovarian failure (POF). The proband underwent menarche at age 12 years and had irregular menstrual cycles, ranging from 20 to 60 days. Hormonal contraception was started at age 16 for menorrhagia, and after cessation 4 years later, her menstrual cycles were even more irregular, ranging from 21 to 140 days. At age 24, she developed hot flushes and oligomenorrhea. Hormone analysis showed elevated follicle-stimulating hormone (FSH; see 136530) and low anti-mullerian hormone (AMH; 600957) levels, and she was diagnosed with primary ovarian insufficiency. The proband's sister, who also underwent menarche at age 12 years but had regular menses with 23-day cycles, developed hot flushes and oligomenorrhea at age 20. Evaluation revealed elevated FSH with low estradiol (E2) and AMH levels. She also had elevated prolactin (PRL; 176760), and brain MRI showed a suspected 3-mm pituitary adenoma that was treated with the dopamine agonist bromocriptine (Parlodel). Hormone stimulation was initiated at age 23 with poor results, but 6 months later she spontaneously conceived and ultimately gave birth to a healthy child. Both patients had normal pubic and axillary hair, breast development, and external genitalia; however, ultrasound revealed small ovaries with a reduced number of follicles. Their unaffected mother reported regular menses at age 47 years.
Jaillard et al. (2020) reported a woman with POF and mutation in the FANCM gene. The proband (patient 5) underwent menarche at age 11 years and experienced secondary amenorrhea at age 25 years. She had elevated FSH and low AMH levels. Pelvic ultrasound showed a normal uterus, but small ovaries without follicles. Cytogenetic analysis after mitomycin C induction revealed increased rates of chromosome breakages and rearrangements in the proband compared to control. An older sister was also diagnosed with POF at 30 years of age.
Heddar et al. (2022) reported 3 Finnish women (patients 192, 305, and 306) and 2 European women (patients 167 and 326) with POF and mutation in the FANCM gene. Limited clinical information was provided, but the 3 Finnish women were tabulated as having primary amenorrhea, whereas patient 167 had secondary amenorrhea at age 18 years, and patient 326 had oligomenorrhea at age 20.
The transmission pattern of POF15 in the family reported by Fouquet et al. (2017) was consistent with autosomal recessive inheritance.
In 2 Finnish sisters with POF, who were negative for mutation in the FRM1 gene (309550), Fouquet et al. (2017) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the FANCM gene (Q1701X; 609644.0005). Their unaffected parents and brother were heterozygous for the mutation.
By whole-exome sequencing in a cohort of 10 women with POF, Jaillard et al. (2020) identified 1 proband (patient 5) who was compound heterozygous for nonsense mutations in the FANCM gene: the previously reported R1931X mutation (609644.0006), and an R1030X mutation (609644.0008). The mutation status of the proband's affected older sister was not reported.
By targeted or whole-exome sequencing in an international cohort of 375 women with POF from 70 families, Heddar et al. (2022) identified 3 Finnish women (patients 192, 305, and 306) and 2 European women (patients 167 and 326) who had mutations in the FANCM gene: all carried the previously reported nonsense mutation Q1701X, for which the 3 Finnish women were homozygous. Patients 167 and 326 were compound heterozygous for Q1701X and a missense mutation, G510S (609644.0009) or Q192L (609644.0010), respectively.
Fouquet, B., Pawlikowska, P., Caburet, S., Guigon, C., Makinen, M., Tanner, L., Hietala, M., Urbanska, K., Bellutti, L., Legois, B., Bessieres, B., Gougeon, A., Benachi, A., Livera, G., Rosselli, F., Veitia, R. A., Misrahi, M. A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency. eLIFE 6: e30490, 2017. Note: Electronic Article. [PubMed: 29231814] [Full Text: https://doi.org/10.7554/eLife.30490]
Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others. Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine. EBioMedicine 84: 104246, 2022. [PubMed: 36099812] [Full Text: https://doi.org/10.1016/j.ebiom.2022.104246]
Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W. A., Beaumont, M., Harrisson, C., Jaaskelainen, T., Palvimo, J. J., Robevska, G., Launay, E., and 16 others. New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing. Maturitas 141: 9-19, 2020. [PubMed: 33036707] [Full Text: https://doi.org/10.1016/j.maturitas.2020.06.004]