Genetically isolated populations
Implications for genetic care
Mathijssen, I.B.
Publication date
2018
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Citation for published version (APA):
Mathijssen, I. B. (2018). Genetically isolated populations: Implications for genetic care.
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Inge B Mathijssen, Astrid S Plomp, Frank Baas, Quinten Waisfisz, Abeltje M Polstra, Hanne Meijers-Heijboer, Mariëlle Alders
Submitted
Further delineation of the phenotype caused by mutations
in the PSMC3IP gene
ABSTRACT
Study question
What is the genetic cause of XX female gonadal dysgenesis (XX-GD) in several women from a Dutch genetically isolated population and do homozygous mutations in the identified gene cause male infertility, and do heterozygous mutations contribute to breast and ovarian cancer predisposition?
Summary answer
We identified a homozygous mutation in PSMC3IP as the cause of XX-GD, but we did not find evidence that a homozygous PSMC3IP mutation causes male infertility, nor that a heterozygous mutation in this gene contributes to breast and ovarian cancer predisposition.
What is known already
XX-GD is a genetically heterogeneous disorder in which in the majority of patients the underlying etiology is unknown. A homozygous mutation in PSMC3IP causing XX-GD has been described in only one family before. Heterozygous variants in PSMC3IP have previously been associated with breast or ovarium cancer predisposition.
Study design, size, duration
This study was performed on six women with XX-GD, their brothers, 42 men with azoospermia or severe oligozoospermia, and 754 non-selected adult controls, all origi-nating from the same Dutch genetically isolated village.
Participants/materials, setting, methods
Genome-wide homozygosity mapping followed by candidate gene Sanger sequencing was used for molecular diagnosis of the XX-GD. In addition we tested the brothers of these patients, as well as men with azoospermia or severe oligozoospermia, and non-selected adult controls from the genetically isolated population on the identified PSMC3IP mutation. Furthermore, we obtained the absolute numbers and crude inci-dence rates of breast cancer (in woman and men) and ovarian cancer between 1995 and 2014 in this population and in the general Dutch population.
Main results and the role of chance
We identified six women with XX-GD traced back to common ancestors 11 genera-tions ago. Homozygosity mapping in four women revealed PSMC3IP as a candidate
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gene. All tested cases carried an identical homozygous mutation c.74G>C; p.(Arg25Pro) in PSMC3IP. The PSMC3IP mutation was not found homozygous in the brothers of the patients, nor in 42 men with azoospermia or oligozoospermia from the genetically isolated population. The carrier frequency in the genetically isolated population is 4.4%. No increased incidence rates for breast cancer or ovarian cancer were demonstrated in the genetically isolated population compared to the general Dutch population.
Limitations, reasons for caution
Further studies are needed to confirm that homozygous mutations in PSMC3IP are not associated with male infertility nor that heterozygous mutations contribute to breast and ovarian cancer predisposition.
Wider implications of the findings
To the best of our knowledge, this is the second report of mutations in this gene causing XX-GD. Our results will provide more insights into the phenotype of homozygous and heterozygous PSMC3IP mutations.
INTRODUCTION
XX female gonadal dysgenesis (XX-GD [MIM 233300]) is a genetically heterogeneous disorder characterized by primary amenorrhea, lack of secondary sexual characteris-tics, streak gonads, hypoplastic uterus, and hypergonadotropic hypogonadism. Several genetic causes of XX-GD have been identified, including mutations in the follicle-stim-ulating hormone receptor gene (FSHR [MIM 136435]), bone morphogenetic protein 15 (BMP15 [MIM 300247]), and nuclear receptor subfamily 5 group A member 1 (NR5A1 [MIM 184757]). However, in the majority of patients with XX-GD, the underlying etiology is unknown.
In 2011 a homozygous 3bp deletion in PSMC3IP (Proteasome 26S ATPase subunit 3-interacting protein) was identified in a highly consanguineous Arab Palestinian family with at least five female patients affected by XX-GD.1 PSMC3IP is also known as HOP2 (Homologous-pairing protein 2 homolog), TBPIP (Tat-binding protein 1-interacting protein), and GT198. The gene is essential for proper homologous chromosome pairing and recombination during meiosis.2 Also, the protein encoded by this gene stimu-lates transcription mediated by estrogen, progesterone, androgen, thyroid hormone, and glucocorticoid receptors.3 Female Psmc3ip knockout mice are infertile and show ovarian tubulostromal hyperplasia with absence of follicles.2 Male Psmc3ip knockout mice are infertile, develop testicular hypoplasia with hyperplasia of interstitial cells and have only primary spermatocytes as the most advanced spermatogenic cells.2 The lack of mature gametes in both sexes of Psmc3ip knockout mice is consistent with a role for the Psmc3ip protein in meiosis. Heterozygous mice of both sexes are fertile with no obvious reproductive abnormalities.2
No mutations in PSMC3IP were identified in a Swedish cohort of 50 female patients with primary ovarian insufficiency4 and in a patient with Perrault syndrome.5 In a group of 18 Japanese patients with azoospermia caused by meiotic arrest, no clear pathogenic mutation was identified in PSMC3IP.6
As PSMC3IP is upregulated in breast cancer,7,8 is involved in DNA recombination path-ways,2 and stimulates DNA strand exchange,9,10 it may be a candidate gene for familial breast and ovarian cancers (HBOC). Two research groups screened for germline muta-tions in PSMC3IP in HBOC patients. They identified germline variants in PSMC3IP in low frequency and proposed that mutations in PSMC3IP potentially contribute to an increased risk in familial breast and ovarian cancers.11,12
Here, we describe a novel founder mutation in PSMC3IP as a cause of XX-GD in females in a Dutch genetically isolated population. To the best of our knowledge, this is the second report of mutations in this gene causing XX-GD.
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METHODS
Patients
All patients live in a genetically isolated village in the northwestern part of the Neth-erlands, which was founded in the 14th Century by 7 to 20 families and has currently about 21,500 inhabitants. Informed consent was given by all subjects included in this study. Medical records were retrieved and family history was obtained.
Genetic analysis
We obtained blood samples of all patients and extracted DNA from peripheral blood lymphocytes by standard procedures. To proof monozygosity of twins (patient 5 and 6), we performed genotyping using 16 polymorphic markers (PP16 kit Promega). For homozygosity mapping in four patients affected with XX-GD (patient 1, 2, 4, and 5 in Figure 1), an Affymetrix Cytoscan HD SNP array was used. For each patient regions of homozygosity larger than 1 Mb were determined followed by identification of regions of homozygosity shared by all four patients. In addition whole exome sequencing was performed in patient 3. Overlapping regions of homozygosity were analyzed for candidate genes (“Genomic Oligoarray and SNP array evaluation tool v1.0”).13 Sanger sequencing of the coding region and flanking intronic regions of the candidate genes PSMC3IP and DMRTA2 (primer details available on request) was performed on an ABI 3730 type DNA analyzer (Applied Biosystems). Parents and brothers of the patients were tested for the PSMC3IP mutation c.74G>C; p.(Arg25Pro) (NM_016556.3) by Sanger sequencing, when possible. Subsequently, a cohort of 42 men with azoospermia or severe oligozoospermia from the genetically isolated population (selected by postal code) was tested for the same PSMC3IP mutation by Sanger sequencing. In addition, we anonymously tested 754 non-selected adult controls from the genetically isolated population for this PSMC3IP mutation using a TaqMan assay.
Breast and ovarian cancer incidences
To determine whether there is a higher incidence of breast cancer and ovarian cancer amongst people from the genetically isolated population, we obtained the absolute numbers and crude incidence rates of breast cancer (in woman and men) and ovarian cancer that were registered by the Integraal Kankercentrum Amsterdam (IKA) between 1995 and 2014 in this population. Also, the same data of the general population of the Netherlands were obtained.14 We compared the crude incidence rates per 5 year age group and the total crude incidence rates between these groups.
RESULTS
Patients
Patient 1 is a 27 years old woman who was referred to the department of Clinical Genetics because of primary amenorrhea of unknown cause. At the age of 10 years pubic and axillary hair started to grow. She started with oral contraceptives at the age of 13 years because of her tall stature and developed regular withdrawal bleedings. When she stopped with oral contraceptives at the age of 17 years, she stopped menstruating and developed frequent hot flashes. Laboratory investigations showed hypergonado-tropic hypogonadism (LH 28 U/L (N 2.0-20), FSH 50 U/L (N 2.0-10.0), estradiol 125 pmol/L (N <210)). Abdominal ultrasound showed a small atrophic uterus with a length of 3 cm and undetectable ovaries. Currently, she is trying to become pregnant with egg donation. Her height is 1.92 m and span 1.94 m. Her breasts are normally developed under hormone replacement therapy. No other health problems are present. A sister of her mother had breast cancer at the age of 44 years. No other family members (up to the third degree) are known with breast or ovarian cancer.
Patient 2 is a 30 years old woman. Puberty started late; she developed secondary sex characteristics at age 16 years and had a growth spurt at age 17 years. When she was 18 years old she visited the gynecologist because of primary amenorrhea and hypergonado-tropic hypogonadism. An MRI showed a small uterus and undetectable ovaries. At 28 years of age she gave birth to a healthy daughter conceived with a donor egg from her sister. Her height is 1.74 and span 1.73 m. Her breasts are normally developed under hormone replacement therapy. Pubic and axillary hair is normal. No other health prob-lems are present. No family members are known with breast or ovarian cancer (up to the third degree).
Patient 3 is a 33 years old woman. From an early age she had irritable bowel syndrome and sensorineural hearing loss in the high tones. At the age of 15 years she was evaluated by an endocrinologist because of absence of breast development, no menstruation and hypergonadotropic hypogonadism. Breast development, pubic hair, and axillary hair were at Tanner stage 1, 4, and 2 respectively. Abdominal ultrasound revealed a small uterus (3.6 x 0.4 cm) and undetectable ovaries. Ovarian biopsies were performed, which showed streak gonads. On hormonal replacement therapy she developed normal breasts and menstruation. When she was 27 years old she gave birth to a healthy daughter conceived with a donor egg and at age 29 years to twins after egg donation. Her current height is 1.86 m. No family members are known with breast or ovarian cancer (up to the third degree).
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spurt at a late age. The height of all three patients is 1.71 m. The span is 1.82, 1.80, and 1.80 m. The breasts of the twin sisters are normally developed under hormone replace-ment therapy. The oldest sister had hormone replacereplace-ment therapy for only a couple of months. Her breasts are at Tanner stage 3. They all have osteoporosis. One sister of the mother of these three patients had breast cancer at the age of 75 years. No other family members are known with breast or ovarian cancer.
In all 6 women, initially no cause of the primary amenorrhea was found. Karyotype in all women was normal and DNA analysis of the FMR1-gene (fragile-X syndrome) in patients 1 and 2 showed no CGG repeat expansion.
The pedigree of all patients is shown in Figure 1.
Figure 1. Co-segregation of a mutation in PSMC3IP with XX female gonadal dysgenesis in a Dutch
Genetic analysis
DNA analysis confirmed the monozygosity of the twins (patient 5 and 6). Homozy-gosity mapping in four patients (patients 1, 2, 4, 5) with XX-GD from the geneti-cally isolated village identified 13 overlapping regions of homozygosity ranging in size from 273 kb to 6,6 Mb and containing approximately 307 annotated genes. Sanger sequencing of the only candidate gene for XX-GD, the PSMC3IP gene, revealed a novel homozygous missense mutation [NM_016556.3: c.74G>C; p.(Arg25Pro); Figure 2] in the four patients included in the homozygosity mapping, as well as patient 3 and 6. In addition, analysis of the WES data of patient 3 did not identify any other pathogenic variants in the overlapping regions of homozygosity nor in other regions. Segregation analysis within the families revealed that the parents and both brothers of patient 3 are heterozygous for the PSMC3IP mutation. Of the five fertile brothers of patients 4, 5, and 6, four are heterozygous for the mutation and one does not carry the mutation. The mutation was present in 7 of 126,594 alleles of the European population and absent in other populations (http://gnomad.broadinstitute.org). The amino acid
Figure 2. Six individuals diagnosed with XX-GD carry the same homozygous missense mutation in the
PSMC3IP gene. (a) Schematic diagram of protein domains encoded by PSMC3IP and the location of the
mutation identified in this study and in the previous study.1 Numbers indicate amino acids.21(b) Sequence
analysis reveals the mutation NM_016556.3: c.74G>C; p.(Arg25Pro) in PSMC3IP. Wildtype (WT) control, heterozygous (HE) mutant, and homozygous (HO) affected woman. (c) Multispecies alignment of the
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change was predicted to be potentially pathogenic by various bioinformatics tools: PhyloP: 5.77 [-14.1;6.4] (highly conserved); Mutation Taster: disease causing, prob: 0.999999997375584; Polyphen: probably damaging (HumVar score 0.999), SIFT: deleterious (score: 0.01, median: 3.32).
All 6 cases had common ancestors traced back 11 generations (Figure 1). The PSMC3IP mutation was not found homozygous in 42 men with azoospermia or oligozoospermia from the genetically isolated village. Genetic testing of 754 non-selected controls from the village revealed one homozygous male and 31 heterozygous carriers, resulting in a carrier frequency of 4.4% in this region and an allele frequency of 2.2%.
Breast and ovarian cancer incidences
Between 1995 and 2014, in total 229 men and women from the genetically isolated village were registered because of treatment for breast cancer and 31 women for ovarian cancer. The crude incidence rates of breast cancer and ovarian cancer per 5 year age group in the genetically isolated population and the general Dutch population between 1995 and 2014 are displayed in Figure 3 and Supplementary Table 1. In most age groups, the crude incidence rates of breast cancer and ovarian cancer seem to be lower in the genetically isolated village than in the general Dutch population.
Overall, the mean crude incidence rate of breast cancer in the genetically isolated
popu-Figure 3. Crude incidence rates of breast cancer per 5 year age group in the genetically isolated
lation is 56.2/100,000 compared to 74.7/100,000 in the general Dutch population (CR ratio 0.75). If age-standardized to the European standard population (European Standardized Rates (ESR)), these rates are 53.7/100,000 and 63.4/100,000 respectively (ESR ratio 0.85).
The mean crude incidence rate of ovarian cancer in the genetically isolated population is 15.2/100,000 compared to 15.5/100,000 in the general Dutch population (CR ratio 0.98). If age-standardized to the European standard population (European Standardized Rates (ESR)), these rates are 14.1/100,000 and 12.6/100,000 respectively (ESR ratio 1.12).
DISCUSSION
All six women described in this paper have the classical features of XX-GD consisting of lack of spontaneous breast development, primary amenorrhea, uterine hypoplasia, streak gonads, and hypergonadotropic hypogonadism. They had spontaneous pubic and axillary hair growth, reflecting the production of androgens by the suprarenal gland, and exhibited prolonged growth and have long arms because of delayed closure of epiphyseal growth plates as the result of estrogen deficiency. In two women successful pregnancies were achieved with oocyte donation. The XX-GD in six females is caused by a homozy-gous missense mutation in the N-terminal domain of PSMC3IP.
The clinical and laboratory features are comparable with the features described in the five patients by Zangen et al.1 These patients have a homozygous 3bp deletion in the C-terminal acidic domain. The ovarian dysgenesis phenotype in these patients is thought to be related to impaired estrogen-dependent transcription.1
Mutations in genes responsible for XX-GD may also cause less severe phenotypes, including primary or secondary amenorrhea with normal sex characteristics or even oligomenorrhea or anovulation. For some genes involved in XX-GD, this continuum of clinical phenotypes has already been described. Mutations resulting in total FSH receptor (FSHR) inactivation cause XX-GD, whereas mutations in FSHR resulting in partial reduction of the FSHR function cause primary or secondary amenorrhea with normal secondary sex characteristics.15 Mutations in BMP15 are also thought to cause a spectrum of phenotypes ranging from ovarian dysgenesis to premature ovarian failure.16,17
The PSMC3IP mutation in the genetically isolated population as well as the mutation described by Zangen at al.1 result in the severe end of the spectrum (XX-GD). Further studies in patients with less severe phenotypes may also reveal mutations in this gene.
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Patient 3 was first believed to have Perrault syndrome because of the symptoms of XX-gonadal dysgenesis combined with sensorineural hearing loss. Moreover, in the same genetically isolated population, recently a homozygous missense mutation in the mitochondrial gene ERAL1 causing Perrault syndrome was identified.18 This ERAL1 mutation was not identified in patient 3, but she eventually turned out to be homozy-gous for the PSMC3IP founder mutation, suggesting that her hearing loss has a separate cause. Recently, another patient with a clinical diagnosis of Perrault syndrome caused by the co-occurrence of homozygous variants in two unlinked genes, responsible for hearing loss (CLDN14) and primary ovarian insufficiency (SGOS2), was described.19 In patients with the clinical diagnosis Perrault syndrome, separate causes of the hearing loss and ovarian insufficiency should be considered, especially in genetically isolated popula-tions and/or highly consanguineous families in which the chance of having autosomal recessive disorders is higher.
As male Psmc3ip knockout mice are infertile, develop testicular hypoplasia, and have only primary spermatocytes as the most advanced spermatogenic cells, PSMC3IP is a candidate to cause human spermatogenic defects.2 However, the PSMC3IP mutation was not found homozygous in patients with azoospermia or oligozoospermia from the genetically isolated population. Thus homozygous PSMC3IP mutations do not seem to be a major cause of male infertility in this population. We identified one homozygous male in a group of anonymous non-selected adult controls, confirming that a homozy-gous mutation in PSMC3IP is non-lethal. As this group was anonymously tested, we have no further details about the fertility of this homozygous male.
Most genes are either causing XX-GD or disruption in spermatogenesis. Genes primarily affecting the gonadal function in females as well as in males are scarce. This also applies to genes involved in meiosis. Spermatogenesis frequently appears to be more severely compromised than oogenesis.20
Both similarities and differences between mice and humans in fertility have been described. To our knowledge, until now no mutations are known to cause infertility in both male and female mice, but only human infertility in females, and not in males. Whether mutations in PSMC3IP cause disruption in spermatogenesis in men remains to be elucidated.
PSMC3IP has previously been described as a potential gene for HBOC as PSMC3IP is upregulated in breast cancer,7,8 is involved in DNA-recombination pathways,2 and stimulates DNA strand exchange.9,10 We therefore investigated whether there is a higher
incidence of these types of cancer in the pedigrees of homozygous XX-GD patients and amongst people from the entire genetically isolated population, as it is expected that about 900 inhabitants are carrier for the PSMC3IP mutation. In the four (large) pedi-grees of the homozygous patients only two family members (up to the third degree) were known with breast or ovarian cancer. Moreover, the mean crude incidence rates of breast and ovarian cancer in the genetically isolated population are not higher (and for breast cancer probably even lower) than in the general Dutch population. From our research in this genetically isolated population, we did not find evidence that this PSMC3IP mutation contributes to breast and ovarian cancer predisposition. It is difficult to make definite conclusions as the absolute numbers of patients with breast- or ovarian cancer in the genetically isolated population are small and it is possible that there is a co-incidence with one or more protective genes or environmental factors. In addition the functional effect of this variant and variants linked to tumor risk may be different (for example loss of function versus gain of function).
In two studies, germline variants in PSMC3IP were reported in a low frequency in HBOC patients.11,12 Both studies, however, have several limitations. In the majority of patients no segregation analysis has been performed. Furthermore, it is unclear whether the amount of variants identified in HBOC patients is higher than in controls. More-over, in the study of Peng et al.,11 DNA-analysis of pathogenic variants in other genes involved in susceptibility to cancer (other than BRCA1/2) is not mentioned, although several pedigrees could well fit with other tumor syndromes. Although the index patients in the study of Schubert et al.12 were screened for pathogenic variants in additional risk genes for HBOC, several important genes, e.g. PTEN, are lacking.
Based on our findings and the limitations of the above mentioned studies, it is uncertain that germline variants in PSMC3IP contribute to an increased risk of breast and ovarian cancer.
In conclusion, we identified a homozygous founder mutation in PSMC3IP as a cause of XX-GD in six females in a Dutch genetically isolated population and found so far no evidence that a homozygous mutation in this gene mutation causes male infertility, nor that this heterozygous mutation contributes to breast and/or ovarian cancer predisposition.
CONFLICT OF INTEREST
The authors declare no conflict of interest. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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ACKNOWLEDGEMENTS
The authors thank the patients who participated in the study and the registration team of the Netherlands Comprehensive Cancer Organization (IKNL) for the collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice.
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