Clinical characteristics.

MCM8/MCM9-related syndromes are characterized by primary gonadal insufficiency (hypergonadotropic hypogonadism) and increased risk of early-onset germ cell tumors in females. Hypergonadotropic hypogonadism can present in females as primary amenorrhea, secondary amenorrhea/oligomenorrhea, underdeveloped uterus, or small/streak ovaries, and in males as impaired spermatogenesis (nonobstructive azoospermia, oligospermia, or Sertoli cell-only syndrome); incomplete or delayed pubertal development is more often seen in females. MCM9-related syndrome is also associated with increased susceptibility to colorectal polyposis (adenomas, hyperplastic or sessile serrated polyps), early-onset colorectal cancer (CRC), and early-onset gastric cancer.

Diagnosis/testing.

The diagnosis of an MCM8/MCM9-related syndrome is established in a proband with a clinical phenotype consistent with MCM8/MCM9-related syndromes and biallelic pathogenic variants in MCM8 or MCM9 identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment of primary gonadal insufficiency in females includes puberty induction when indicated, estrogen replacement with progestogen in those with a uterus, and management of primary ovarian insufficiency sequelae; in males, management of spermatogenic failure; early referral to reproductive endocrinology / infertility specialist; standard treatments for germ cell tumors; polyp resection during colonoscopy; subtotal colectomy or proctocolectomy when needed; standard treatments for colorectal and gastric cancer.

Surveillance: Annual evaluation by pediatric endocrinologist / reproductive endocrinologist / gynecologist (females) or andrologist/urologist (males) to assess pubertal progression, adequacy of / adherence to hormone therapy, symptoms of sex steroid deficiency, and fertility planning needs; bone density scan every one to three years for those with low bone mineral density, otherwise frequency based on risk factors for low bone mineral density; measure blood pressure and assess weight, body mass index, and smoking status at least annually; lipid panel, fasting blood glucose, and hemoglobin A1c as needed; consider annual pelvic ultrasound in females from age ten to 20 years; consider colonoscopy, upper endoscopy, and Helicobacter pylori testing every two years beginning at age 25 years for those with biallelic MCM9 pathogenic variants.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with an MCM8/MCM9-related syndrome in order to identify as early as possible those who may benefit from treatment of primary ovarian insufficiency, delayed puberty, reduced fertility, and cancer surveillance.

Genetic counseling.

MCM8/MCM9-related syndromes are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an MCM8 or MCM9 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes may have reduced fertility. To date, it is not clear that heterozygotes are at increased risk of CRC or polyposis. Once the MCM8 or MCM9 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

MCM8/MCM9-related syndromes should be suspected in probands with the following clinical findings and family history.

Clinical findings in MCM8/MCM9-related syndromes

• Primary gonadal insufficiency (hypergonadotropic hypogonadism)
  • Primary amenorrhea, secondary amenorrhea/oligomenorrhea in females; underdeveloped uterus and small/streak ovaries on pelvic ultrasound in some females
  • Impaired spermatogenesis in males: nonobstructive azoospermia, oligospermia, Sertoli cell-only syndrome
  • Delayed or incomplete puberty (most often reported in females)
• Germ cell tumors diagnosed before age 20 years in some females

Clinical findings in MCM9-related syndrome

• History of ≥20 colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age, or colorectal polyposis (i.e., 10-20 adenomas) in an individual with any other suggestive findings
• Colorectal cancer diagnosed before age 50 years
• Gastric cancer diagnosed before age 50 years

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MCM8/MCM9-related syndromes is established in a proband with a clinical phenotype consistent with MCM8/MCM9-related syndromes and biallelic pathogenic (or likely pathogenic) variants in MCM8 or MCM9 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic MCM8 or MCM9 variants of uncertain significance (or of one known MCM8 or MCM9 pathogenic variant and one MCM8 or MCM9 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

MCM8/MCM9-related syndromes are characterized by primary gonadal insufficiency (hypergonadotropic hypogonadism), incomplete or delayed pubertal development, and increased risk of early-onset germ cell tumors in females [Alvarez-Mora et al 2020, Helderman et al 2025]. MCM9-related syndrome is also associated with increased susceptibility to colorectal polyposis, early-onset colorectal cancer, and gastric cancer. To date, 54 individuals (26 with MCM8-related syndrome and 28 with MCM9-related syndrome) have been reported in the literature [Wood-Trageser et al 2014, AlAsiri et al 2015, Goldberg et al 2015, Tenenbaum-Rakover et al 2015, Dou et al 2016, Fauchereau et al 2016, Bouali et al 2017, Desai et al 2017, Jolly et al 2019, Terradas et al 2019, Yang et al 2019, Alvarez-Mora et al 2020, França et al 2020, Golubicki et al 2020, Guo et al 2020, Heddar et al 2020, Jin et al 2020, Liu et al 2020, Wang et al 2020, Zhang et al 2020, Goldberg et al 2021, Shen et al 2021, Soares de Lima et al 2021, Turkyilmaz et al 2021, Kherraf et al 2022, Tucker et al 2022, Potorac et al 2023]. Individuals reported to date were curated from the literature and summarized by Helderman et al [2025], who only included individuals with biallelic pathogenic and likely pathogenic variants (n=15 for MCM8; n=22 for MCM9) as well as variants of uncertain significance (VUS) with a combined annotation-dependent depletion (CADD) score higher than 20 and a gnomAD allele frequency lower than 1% (n=11 for MCM8; n=6 for MCM9). The following description of the phenotypic features associated with these conditions is based on these data. These reports should be interpreted in light of potential ascertainment bias, as most individuals were identified through fertility-focused studies rather than cancer cohorts, likely explaining the high prevalence of primary gonadal insufficiency.

Note: Unless otherwise specified, data and information do not apply to MCM8/MCM9 heterozygotes and individuals with biallelic variants of uncertain significance that do not pass the pathogenicity filtering (CADD score higher than 20 and a gnomAD allele frequency lower than 1%).

Primary gonadal insufficiency (hypergonadotropic hypogonadism) is the most consistent phenotypic feature associated with biallelic MCM8 or MCM9 variants. In the largest aggregated cohort, gonadal dysfunction was reported in 88% of individuals with biallelic MCM8 pathogenic variants (23/26) and 93% with biallelic MCM9 pathogenic variants (26/28), typically recognized between ages ten and 30 years; these proportions may be inflated by ascertainment through fertility-focused studies [Helderman et al 2025].

Females typically present with primary ovarian insufficiency, which may manifest as absent puberty, delayed or incomplete pubertal development, primary amenorrhea, or secondary amenorrhea/oligomenorrhea after spontaneous menarche. Underdeveloped uterus and small/streak ovaries on pelvic ultrasound are common (particularly prior to estrogen exposure) [Wood-Trageser et al 2014, AlAsiri et al 2015, Bouali et al 2017, Wang et al 2020].

Males most often present with infertility due to impaired spermatogenesis. The spectrum of spermatogenic phenotype includes azoospermia to severe oligospermia/oligoasthenospermia. Semen parameters can fluctuate with age and intercurrent factors (smoking, obesity, stress, exposure to heat). Sertoli cell-only syndrome (complete absence of germ cells on testicular biopsy) has been reported in some males [Tenenbaum-Rakover et al 2015, Kherraf et al 2022, Potorac et al 2023]. Note: The presence of sperm – even with apparently normal parameters on a single evaluation – should not be used to exclude MCM8/MCM9-related syndromes, particularly if the broader clinical picture (e.g., hypergonadotropic hypogonadism, family history consistent with autosomal recessive inheritance) remains suggestive.

Short stature has been reported in individuals with pubertal delay due to an MCM8/MCM9-related syndrome. Final adult height is affected by age at treatment initiation and adherence to hormone therapy [Wood-Trageser et al 2014, França et al 2020, Guo et al 2020, Wang et al 2020, Turkyilmaz et al 2021].

Germ cell tumors have only been reported in females, including two individuals with biallelic MCM8 pathogenic variants and one individual with biallelic MCM9 pathogenic variants [Alvarez-Mora et al 2020, Helderman et al 2025]. Reported tumors include endodermal sinus tumors, dysgerminomas, and gonadal tumors arising in the setting of marked gonadal dysgenesis. These tumors have occurred in childhood and adolescence (age range: 11 to 15 years) [Helderman et al 2025].

Thyroid dysfunction (including hypothyroidism) has been reported in three individuals with biallelic MCM8 variants. Two individuals had primary hypothyroidism; the third individual had hypothyroidism identified in childhood and had normal thyroid-stimulating hormone and free T₄ levels at the time of evaluation but persistent anti-TPO (thyroid peroxidase) antibodies [AlAsiri et al 2015, Heddar et al 2020].

Colorectal polyposis has been observed primarily in individuals with biallelic MCM9 variants [Helderman et al 2025]. Polyps were often numerous, frequently exceeding 20 at the time of endoscopic evaluation, with reported histologic types including adenomas and hyperplastic and serrated polyps [Goldberg et al 2015]; age at identification of polyps ranged between 19 and 68 years [Goldberg et al 2021, Helderman et al 2025]. Two previously reported individuals with biallelic MCM8 pathogenic variants subsequently developed colorectal polyps after publication [Helderman et al 2025; N Helderman, unpublished data]. One individual had a sessile serrated lesion and a tubular adenoma with low-grade dysplasia at age 26 years; her 35-year-old sister developed six tubular adenomas with low-grade dysplasia and three hyperplastic polyps [N Helderman, unpublished data]. The prevalence of colorectal polyposis may be underestimated, as many individuals with biallelic MCM8 or MCM9 pathogenic variants were young at the time of diagnosis and/or were not evaluated by colonoscopy.

Colorectal cancer (CRC) is the most frequently reported malignancy in individuals with biallelic MCM9 pathogenic variants, with ages at diagnosis ranging between 30 and 60 years [Goldberg et al 2015, Goldberg et al 2021, Helderman et al 2025]. The prevalence of CRC in individuals with biallelic MCM8 or MCM9 pathogenic variants may be underestimated due to ascertainment bias in this cohort, as cancer risk is age dependent, most individuals were identified through fertility-focused studies, and many did not have longitudinal follow up.

Gastric cancer has been reported in one individual with biallelic MCM9 variants [Helderman et al 2025]. Consistent with this observation, population-level analyses suggest significant enrichment of biallelic MCM9 pathogenic variants among individuals with gastric cancer (odds ratio: 27.03; 95% CI: 2.93-248.5). No enrichment was observed among individuals with biallelic MCM8 pathogenic variants, and no individuals with biallelic MCM8 pathogenic variants with gastric cancer have been reported to date [Helderman et al 2025].

Other findings have been reported in isolated individuals with MCM8/MCM9-related syndromes. Given the limited number of reported individuals, these features should be interpreted with caution but warrant mention. Reported findings include intellectual disability, temporal lobe epilepsy, hearing loss, and unilateral kidney agenesis in one individual [Tenenbaum-Rakover et al 2015]. Another individual presented with facial nevi and a shield-like chest [Wang et al 2020], and pilomatricomas were reported in a further individual [Heddar et al 2020]. At present, it remains unclear whether these features are part of the phenotype or represent coincidental findings.

MCM8/MCM9 heterozygotes. Individuals heterozygous for an MCM8 or MCM9 variant may have reduced fertility. Hypogonadism was observed in 29% (14/49) of individuals with a heterozygous MCM8 pathogenic variant and 22% (10/45) of individuals with a heterozygous MCM9 pathogenic variant [Helderman et al 2025].

CRC and polyposis have been rarely reported in heterozygous individuals (two individuals with CRC and two with polyposis in those with a heterozygous MCM8 pathogenic variant; six individuals with CRC and seven with polyposis in those with a heterozygous MCM9 pathogenic variant, including three individuals having both). CRC onset was at older ages (age >40 years) compared to individuals with biallelic pathogenic variants [Helderman et al 2025]. However, to date there is no clear evidence that heterozygotes are at increased risk of CRC or polyposis.

Phenotype Correlations by Gene

MCM8. To date, CRC has not been reported in individuals with biallelic MCM8 pathogenic variants and only two individuals were found to have colorectal polyposis. In an analysis of the 100,000 Genomes Project, identifying 51 individuals with biallelic pathogenic or predicted deleterious variants in MCM8, no significant enrichment of CRC, polyposis, or other malignancies was observed compared with controls [Helderman et al 2025]. However, prevalence of colorectal phenotypes may be underestimated, as many individuals with biallelic MCM8 pathogenic variants are not routinely evaluated by colonoscopy.

MCM9. To date, individuals with biallelic MCM9 pathogenic variants are more likely to have colorectal polyps compared to individuals with biallelic MCM8 pathogenic variants.

Genotype-Phenotype Correlations

To date, available data are insufficient to establish a genotype-phenotype correlation based on variant type, as both missense and predicted loss-of-function variants have been reported in individuals with overlapping clinical features. However, suspected disease-causing variants were shown to cluster in two key regions: the N-terminal DNA-binding domain, which is crucial for protein-DNA binding (55% of MCM8 variants; 20% of MCM9 variants); and the AAA+ core domain, essential for DNA helicase activity (45% of MCM8 variants; 60% of MCM9 variants) [Helderman et al 2025].

Penetrance

Pedigree studies demonstrate that the penetrance of MCM8/MCM9-related syndromes is nearly complete, as almost all individuals displayed at least one of the reported phenotypes [Helderman et al 2025]. However, two unaffected individuals with biallelic MCM8 pathogenic variants have been reported. Both were phenotypically normal sibs of individuals with MCM8-related syndrome. Importantly, given the absence of extended follow-up data for these individuals, late-onset manifestations cannot be excluded.

Prevalence

The prevalence of MCM8/MCM9-related syndromes is unknown. Population-based data from gnomAD (version 2.1.1) suggest that predicted loss-of-function variants in MCM8 occur at a frequency of approximately 1.4 in 100,000 individuals, with the highest prevalence (5.5 individuals in 100,000 persons) in the African / African American population, and predicted loss-of-function variants in MCM9 occur at a frequency of approximately 2.5 in 100,000 individuals, with the highest prevalence (5.7 individuals in 100,000 persons) in the European Finnish population. Missense variants in MCM8 and MCM9 are found in 462.4 and 1,173.3 individuals in 100,000 persons, respectively. However, it is currently unknown how many of these are (likely) pathogenic. Modeling of biallelic deleterious variants suggests that roughly 0.02% of individuals may have biallelic pathogenic variants in MCM8 or MCM9 [Helderman et al 2025].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an MCM8/MCM9-related syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

Surveillance should be considered within a shared decision-making framework, taking into account the current available evidence. The evaluations summarized in Table 7 are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with an MCM8/MCM9-related syndrome in order to identify as early as possible those who may benefit from treatment of primary ovarian insufficiency (POI), delayed puberty, reduced fertility, and cancer surveillance [Helderman et al 2025].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Individuals with primary gonadal insufficiency / POI have markedly reduced fertility; however, intermittent ovarian function and spontaneous pregnancy can occur in those with POI. Pregnancy achieved spontaneously or through assisted reproductive technologies should be managed by obstetrics providers based on standard obstetric indications and the individual's comorbidities.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

MCM8/MCM9-related syndromes are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an MCM8 or MCM9 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an MCM8 or MCM9 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes may have reduced fertility. To date, it is not clear that heterozygotes are at increased risk for colorectal cancer (CRC) or polyposis (see Clinical Description, MCM8/MCM9 heterozygotes). There are no specific screening recommendations for heterozygous relatives of individuals with an MCM8/MCM9-related syndrome, except for participation in general cancer population screening measures.

Sibs of a proband

• If both parents are known to be heterozygous for an MCM8 or MCM9 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes may have reduced fertility. To date, it is not clear that heterozygotes are at increased risk for CRC or polyposis (see Clinical Description, MCM8/MCM9 heterozygotes). There are no specific screening recommendations for heterozygous relatives of individuals with an MCM8/MCM9-related syndrome, except for participation in general cancer population screening measures.

Offspring of a proband

• The offspring of an individual with an MCM8/MCM9-related syndrome are obligate heterozygotes for a pathogenic variant in MCM8 or MCM9.
• To date, most reported individuals with an MCM8/MCM9-related syndrome have had severe gonadal dysfunction, and natural conception is expected to be uncommon.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an MCM8 or MCM9 pathogenic variant.

Heterozygote Detection

Heterozygote testing for at-risk relatives requires prior identification of the MCM8 or MCM9 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• Females with primary ovarian insufficiency should be counseled that spontaneous conception can occur, and hormone therapy does not provide contraception; effective contraception is needed when pregnancy prevention is desired. Individuals and couples should be offered referral to a reproductive endocrinology / infertility specialist to discuss fertility preservation (when feasible) and assisted reproduction options (e.g., donor gametes, in vitro fertilization, intracytoplasmic sperm injection).
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once the MCM8 or MCM9 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MCM8 and MCM9 encode DNA helicases MCM8 and MCM9, respectively, which are evolutionarily conserved components of a specialized minichromosome maintenance helicase complex that is critical for maintaining genome stability [Helderman et al 2023]. MCM8 and MCM9 interact to form a hexameric helicase ring complex, and functional studies indicate that the MCM8-MCM9 complex participates in multiple molecular processes, including DNA replication, meiosis, homologous recombination (HR), and mismatch repair (MMR) [Helderman et al 2023].

During DNA replication, MCM8-MCM9 may support the origin recognition complex by recruiting stabilizing proteins and, under certain circumstances, promote replication fork progression, particularly in the context of MCM2 through MCM7 dysfunction. By recruiting BRCA1 and RAD51, the complex can also protect replication forks from degradation when stalled. In meiosis and HR, MCM8-MCM9 contributes to the formation of crossover DNA products and the repair of crosslinks, whereas in MMR, it may facilitate DNA unwinding upon recruitment by hMutS, enabling subsequent hMutL recruitment [Helderman et al 2023].

Biallelic loss-of-function variants in MCM8 or MCM9 may disrupt these processes, with impaired meiosis likely underlying infertility and defective HR and MMR, potentially increasing cancer risk. Interestingly, beyond their shared function within the MCM8-MCM9 complex, each protein may also have independent roles in these processes, and additional functions, either together or separately, cannot be excluded. These differences may contribute to the variable clinical phenotypes observed with biallelic MCM8 or MCM9 pathogenic variants.

Studies of tumors from individuals with biallelic MCM8 or MCM9 variants have not yet identified mutational signatures uniquely associated with MCM8 or MCM9 deficiency. Signatures linked to HR and MMR deficiency were observed in only a minority of tumors, whereas clock-like signatures and signatures of unknown etiology were relatively common [Helderman et al 2023]. Further studies are therefore needed to determine whether tumors arising in individuals with biallelic MCM8 or MCM9 variants are molecularly similar to sporadic tumors, or whether additional as yet unrecognized mutational signatures are associated with MCM8 or MCM9 deficiency.

Interestingly, in the Cancer Genome Atlas pan cancer dataset, both mono- and biallelic somatic pathogenic variants in MCM8 and MCM9 have been identified in tumors with mutational signatures associated with ultraviolet exposure, APOBEC activity, MMR deficiency, and POLE deficiency [Helderman et al 2025]. These findings suggest that secondary impairment of the MCM8-MCM9 complex may arise during sporadic tumorigenesis in a subset of cancers characterized by genomic instability resulting from defects in other DNA repair pathways.

Collectively, these data position MCM8 and MCM9 at the intersection of DNA replication, meiosis, HR, and MMR, linking infertility phenotypes with tumor predisposition.

Mechanism of disease causation. Loss of function

Acknowledgments

The authors sincerely thank all individuals and their families for providing consent for the research on which this review is based.

Revision History

• 16 June 2026 (sw) Review posted live
• 27 January 2026 (mn) Original submission

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