A dysmorphic newborn with 45,X,der(1)inv(1)(p13;qter)t(Y;1)(pter-->q11;p13),-Y de novo karyotype

A dysmorphic newborn with 45,x,der(1)inv(1)(p13;qter)t(y;1)(pter-->q11;p13),-Y de novo karyotype: Y/autosome translocations are very rare chromosomal rearrangements. In most cases, the long arm of the Y chromosome is translocated onto an autosome and most patients are referred because of male infertility. Y/1 translocations are very rare, and have been reported in seven patients so far. Pericentric inversions may be seen in all chromosomes and are not associated with phenotypic abnormalities. Here we report a 6-day old male baby with prenatal growth retardation, frontal bossing, hypertelorism, micrognathia, cleft soft palate, absent uvula, hypospadias, simian line in both hands and hammer toes. Cytogenetic analysis was performed with GTG-banding, C-banding and FISH analysis containing X centromeric probe, Yq12-qter locus specific probe and whole chromosome Y probe. An unbalanced Y/1 translocation was diagnosed: 45,X,der(1)inv(1)(p13;qter)t(Y;1)(pter-->q11;p13),-Y.     

46,XX, der(15),t(Y;15)(q12;p11) karyotype in an azoospermic male

We report on a Yq/15p translocation in a 23-year-old infertile male referred for Klinefelter Syndrome testing, who had azoospermia and bilateral small testes. Hormonal studies revealed hypergonadotropic hypogonadism. Conventional cytogenetic procedures giemsa trypsin giemsa (GTG) and high resolution banding (HRB) and molecular cytogenetic techniques Fluorescence In Situ Hybridization (FISH) performed on high-resolution lymphocyte chromosomes revealed the karyotype 46,XX, t(Y;15)(q12;p11). SRY-gene was confirmed to be present by classical Polymerase Chain Reaction (PCR) methods. His father carried de novo derivative chromosome 15 [45,X, t(Y;15)(q12;p11)] and was fertile; the karyotype of the father using G-band technique confirmed a reciprocal balanced translocation between chromosome Y and 15. In the proband, the der (15) has been inherited from the father because the mother had a normal karyotype (46,XX). In the proband, the der (15) could have produced genetic imbalance leading to unbalanced robertson translocation between chromosome Y and 15, which might have resulted in azoospermia and infertility in the proband. The paternal translocation might have lead to formation of imbalanced ova, which might be resulted infertility in the proband. Sister''s karyotypes was normal (46,XX) while his brother was not analyzed.     

Impact of pericentric inversion of Chromosome 9 [inv (9) (p11q12)] on infertility

BACKGROUND:

One of the frequent occurrences in chromosome rearrangements is pericentric inversion of the Chromosome 9; inv (9) (p11q12), which is consider to be the variant of normal karyotype. Although it seems not to correlate with abnormal phenotypes, there have been many controversial reports indicating that it may lead to abnormal clinical conditions such as infertility. The incidence is found to be about 1.98% in the general population.

MATERIALS AND METHODS:

We investigated the karyotypes of 300 infertile couples (600 individuals) being referred to our infertility clinic using standard GTG banding for karyotype preparation.

RESULTS:

The chromosomal analysis revealed a total of 15 (2.5%) inversions, among these, 14 male patients were inversion 9 carriers (4.69%) while one female patient was affected (0.33%). The incidence of inversion 9 in male patients is significantly higher than that of normal population and even than that of female patients (P< 0.05).

CONCLUSIONS:

This result suggests that inversion 9 may often cause infertility in men due to spermatogenic disturbances, which are arisen by the loops or acentric fragments formed in meiosis.     

A complex chromosomal rearrangement with a translocation 4;10;14 in a fertile male carrier: ascertainment through an offspring with partial trisomy 14q13-->q24.1 and partial monosomy 4q27-->q28 [corrected

Complex chromosomal rearrangements (CCRs) are usually associated with infertility or subfertility in male carriers. If fertility is maintained, there is a high risk of abnormal pregnancy outcome. Few male carriers have been identified by children presenting with mental retardation/congenital malformations (MR/CM) or by spontaneous abortions of the spouses. We report a de novo CCR with five breakpoints involving chromosomes 4, 10 and 14 in a male carrier who was ascertained through a son presenting with MR/CM due to an unbalanced karyotype with partial trisomy 14 and partial monosomy 4. The child has a healthy elder brother. In the family history no abortions were reported. No fertility treatment was necessary. Cytogenetic analysis from the affected son showed a reciprocal translocation t(4;10) with additional chromosomal material inserted between the translocation junctions in the derivative chromosome 10. The father showed the same derivative chromosome 10 but had additionally one aberrant chromosome 14. Further molecular cytogenetic analyses determined the inserted material in the aberrant chromosome 10 as derived from chromosome 14 and revealed a small translocation with material of chromosome 4 inserted into the derivative chromosome 14. Thus the phenotype of the son is supposed to be associated with a partial duplication 14q13-->q24.1 and a partial monosomy 4q27-->q28. Including our case we are aware of eleven CCR cases with fertile male carriers. In eight of these families normal offspring have been reported. We propose that exceptional CCRs in fertile male carriers might form comparatively simple pachytene configurations increasing the chance of healthy offspring.     

The fragile site on chromosome 16 (q21q22)

Summary The significance of the fragile site on 16 (q21q22) has not yet been fully evaluated. New data will contribute to the understanding of this cytogenetic finding. Therefore we report on four families where a chromosome 16 with fragile site was segregating and such problems as infertility, abortions, malformations, and ancuploidy were present. The hypothesis that this fragile site is a site of viral modification (or integration?) is considered.     

Balanced reciprocal translocation t(5;13)(q33;q12) and 9q31.1 microduplication in a man suffering from infertility and pollinosis

We describe the first case of two chromosomal abnormalities, balanced reciprocal translocation t(5;13)(q33;q12.1) and a microduplication in the region 9q31.1, in a man suffering from infertility and pollinosis. In the region 13q12.1 is located the TUBA3C (tubulin, alpha 3c) gene, which plays an important dynamic role in the motility of flagella. This case might support the opinion that haploinsufficiency of the TUBA3C gene could be the cause of sperm immotility and abnormal sperm morphology, resulting in infertility in the patient. Single-nucleotide polymorphism (SNP) array analysis revealed a novel 9q31.1 microduplication inherited from both parents, which contributes to the genomic instability.     

Exceptional complex chromosomal rearrangement and microdeletions at the 4q22.3q23 and 14q31.1q31.3 regions in a patient with azoospermia

In this report we describe the first patient ever found to have azoospermia in association with both exceptional complex chromosomal rearrangements and microdeletions at two translocation breakpoints. A 36-year-old male who had been suffering from male factor infertility was admitted to our clinic. The patient also displayed mild dysmorphia. An analysis of the patient's semen revealed azoospermia. GTG banding revealed the presence of an exceptional complex chromosomal rearrangement involving chromosomes 1, 4, 10 and 14. Using subtelomeric FISH analysis, the patient's karyotype was designated as 46,XY,t(1;10)(q43q44;q21q26.1)(CEB108/T7+,D1S3738-;10PTEL006+,D10S2290+, D1S3738+), ins(14;4) (q31.3;q23q33)(D14S1420+; D4S3359+, D4S2930+). Array-CGH analysis revealed two microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions. We suggest that microdeletions at the 4q22.3q23 and 14q31.1q31.3 chromosomal regions associated with both an exceptional complex chromosomal rearrangement and the Homo sapiens chromosome 4 open reading frame 37 (C4orf37) gene located at the 4q22.3q23 region might be associated with male factor infertility.     

Translocation (Y;19)(q12;q13) and azoospermia

An azoospermic male with a 46,X,t(Y;19)(q12;q13) karyotype is described. The comparison with 12 similar cases reveals that the Y breakpoints are usually on the long arm whereas the autosomal ones seem to be at random. Since a premeiotic origin is inconsistent with the arrest at diakinesis seen in those cases with meiotic studies, we postulate that a balanced t(Y;A) arises either via a chromatid exchange in the meiotic interphase or through a chromosome exchange in spermiogenesis or at the one cell stage of the zygote.     

Aquaporins and (in)fertility: More than just water transport

Aquaporins (AQPs) are a family of channel proteins that facilitate the transport of water and small solutes across biological membranes. They are widely distributed throughout the organism, having a number of key functions, some of them unexpected, both in health and disease. Among the various diseases in which AQPs are involved, infertility has been overlooked. According to the World Health Organization (WHO) infertility is a global public health problem with one third of the couples suffering from subfertility or even infertility due to male or female factors alone or combined. Thus, there is an urgent need to unveil the molecular mechanisms that control gametes production, maturation and fertilization-related events, to more specifically determine infertility causes. In addition, as more couples seek for fertility treatment through assisted reproductive technologies (ART), it is pivotal to understand how these techniques can be improved. AQPs are heterogeneously expressed throughout the male and female reproductive tracts, highlighting a possible regulatory role for these proteins in conception. In fact, their function, far beyond water transport, highlights potential intervention points to enhance ART. In this review we discuss AQPs distribution and structural organization, functions, and modulation throughout the male and female reproductive tracts and their relevance to the reproductive success. We also highlight the most recent advances and research trends regarding how the different AQPs are involved and regulated in specific mechanisms underlying (in)fertility. Finally, we discuss the involvement of AQPs in ART-related processes and how their handling can lead to improvement of infertility treatment.     

Association study of folate-related enzymes (MTHFR,MTR, MTRR) genetic variants with non-obstructive male infertility in a Polish population

Spermatogenesis is a process where an important contribution of genes involved in folate-mediated one-carbon metabolism is observed. The aim of the present study was to investigate the association between male infertility and the MTHFR (677C > T; 1298A > C), MTR (2756A > G) and MTRR (66A > G) polymorphisms in a Polish population. No significant differences in genotype or allele frequencies were detected between the groups of 284 infertile men and of 352 fertile controls. These results demonstrate that common polymorphisms in folate pathway genes are not major risk factors for non-obstructive male infertility in the Polish population.     

Association study of protamine 2 (<Emphasis Type="Italic">PRM2</Emphasis>) gene polymorphism with male infertility in Chinese Han population

Protamine 2 (PRM2), an essential nuclear protein expressed in sperm, is known to be involved in the spermatogenesis. Although PRM2 defects have been reported to be involved in male infertility, studies for the relationship between male infertility and PRM2 polymorphisms are inconclusive. With the purpose to determine the association of PRM2 variant with male infertility in Chinese Han population, one single nucleotide polymorphism locus G398C in PRM2 which might play a role in semen quality was selected and the variant frequency was analyzed in 144 idiopathic infertile men (case group) and 111 proven-fertile men (control group) in the study. Three genotypes were discovered in the studied population and statistical analysis showed that the frequencies of GG and GC genotypes of PRM2 G398C were significantly different between the fertile and infertile men (P < 0.05) and GC genotype was associated with increased risk of male infertility (OR = 1.795, 95 % CI 1.070–3.013, P = 0.026). Further, the C allele distribution was significantly elevated in infertile group (OR = 1.484, 95 % CI 1.001–2.200, P = 0.049). Moreover, we discovered that sperm motility, progressive motility, sperm DNA integrity as well as nuclear maturity rate of GG genotype presented the highest values and were dramatically different with that of CC genotype (P < 0.05). Our results gave the first evidence that PRM2 G398C polymorphism was associated with the pathogenesis of male infertility and its genetic variation was in relation to semen quality in Chinese Han population.     

Pachytene analysis in males heterozygous for a familial translocation (9;12;13) (q22; q22; q32) ascertained through a child with partial trisomy 9

A family with four male and three female heterozygotes for a three-way translocation (9;12;13) (q22; q22; q32) in three generations was ascertained through a chromosomally imbalanced newborn with an additional derivative chromosome 9 resulting from nondisjunction. Three heterozygous males from two generations with apparent differences in their fertility status were investigated using pachytene spreads and testicular histology. Pachytene analysis in all three individuals, the fertile (II-2) as well as the subfertile (III-7) and infertile (III-9), showed a hexavalent with central nonpairing around the translocation breakpoints in nearly all spermatocytes. Thus, the observed hexavalent configurations in pachytene do not seem to have caused impaired fertility. This rather may have been the result of sperm carrying unbalanced chromosome sets. However, the observed difference in fertility between the heterozygous fertile male in generation II and his two heterozygous sons remains unexplained.     

The phenotype in partial 13q trisomies,apropos of a familial (13;15)(q22;q26) translocation

Summary A 12 month-old male patient with a karyotype 46, XY,-15,+der(15),t(13;15)(q22;q26)pat is presented. His stillborn sib showed malformations compatible with the 13q deletion syndrome, probably due to a 46,XY, der(13) karyotype. Phenotypic analysis of 41 cases from the literature with partial distal 13q (D13q) trisomies indicate that the segment 13q22 qter in trisomy with or without another concomitant aneusomy is sufficient to produce the majority of the trisomy 13 syndrome features, some of which (cleft palate, increased HbF and projections in PMN) are present in different non-overlapping partial 13q trisomies. About 82% of the D13q trisomies are inherited, more frequently from the mother.     

The position of t(11;22)(q23;q11) constitutional translocation breakpoint is conserved among its carriers

The t(11;22)(q23;q11) translocation is the most common recurrent balanced translocation described in humans. Carriers are phenotypically normal and often go undetected until diagnosis as a result of infertility investigations or following the birth of chromosomally unbalanced offspring. Efficient diagnostics of t(11;22) is important for children born to carriers of the translocation and for prenatal and pre-implantation diagnosis. The translocation breakpoint on chromosome 22 is located within a region containing low copy repeats, and this site is one of the last unfilled gaps in the sequence of this chromosome. This autosome harbors multiple other low copy repeats, which have been entirely sequenced. We report a combined sequencing and fiber FISH breakpoint characterization in five translocation carriers. From one carrier a cosmid library was constructed, and two chimeric cosmids (cos4_der11 and cos6_der22) were sequenced, which showed that strong palindromes (or inverted repeats) occur on both chromosomes. The translocation breakpoints occur at the tip of both inverted repeats. The palindrome on chromosomes 22 and 11 is composed of 852 and 166 bases, respectively. Four additional carriers were studied using fiber FISH with a resolution limit of 2 kb. Analysis of breakpoints on the DNA sequence level, or at the level of fiber FISH, indicate that they occur at the same position on both chromosomes in all five carriers. Using cos6_der22, PAC 158L19 and BAC 3009A19, we demonstrate that FISH is an attractive alternative in molecular diagnostics of t(11;22), as PCR assays are not reliable, due to the presence of numerous copies of low copy repeats.     

Male infertility, female fertility and extrapair copulations

Females that are socially bonded to a single male, either in a social monogamy or in a social polygyny, are often sexually polyandrous. Extrapair copulations (EPC) have often been suggested or rejected, on both empirical and theoretical grounds, as an important mechanism that enables females to avoid fertility risks in case their socially bonded male is infertile. Here, we explore this possibility in two steps. First, we present a mathematical model that assumes that females have no precopulatory information about male fertility, and shows that a female EPC strategy increases female reproductive success only if certain specific conditions are upheld in the nature of male infertility. In particular, these conditions require both (i) that fertile sperm precedence (FSP) is absent or incomplete within ejaculates of the same male (i.e. that an infertile male is, at least partly, truly infertile), and (ii) the existence of FSP among ejaculates of different males (such that infertile spermatozoa of the infertile male are at a disadvantage when competing against spermatozoa of a fertile male). Second, to evaluate their potential role in the evolution of female EPC, we review the abundance and FSP patterns of the different male infertility types. The conclusion is drawn that some common infertility types, such as poor sperm count or motility, contribute to the evolution of female EPC, whereas other common infertility types, such as sperm depletion or allocation in a social monogamy (but not in a social polygyny), and in particular male driven polyspermy, do not. Also, a deeper look at the arms race between sperm fertilization efficiency and female barriers to sperm may answer the non‐trivial question: “why are some types of infertility so common?”     

Evaluation of <Emphasis Type="Italic">GPx1</Emphasis> Pro198Leu polymorphism in idiopathic male infertility

Infertility is defined as failure to conceive a child after 1 year of unprotected regular sexual intercourse. Approximately half of all cases of infertility are caused by factors related to the male. In nearly 50% of infertile men it is not possible to determine the cause of infertility and this situation has been defined as unexplained or idiopathic. Oxidative stress plays an important role in the pathophysiology of male infertility. Oxidative stress results from an imbalance in free radicals and antioxidant defense mechanisms of the body. Genetic variations in the antioxidant gene coding for GPx enzyme may lead to decreased or impaired regulation of its enzymatic activity and alter reactive oxygen species (ROS) detoxification. We have investigated the possible association between polymorphism GPx1 Pro198Leu and idiopathic male infertility. One hundred patients with idiopathic male infertility and one hundred fifty healthy volunteers were enrolled. Genomic DNA was extracted from blood samples. Genotyping for the GPx1 Pro198Leu polymorphism was done by PCR–restriction fragment length polymorphism (RFLP) using ApaI. The genotype frequencies were 11% (Leu/Leu), 76% (Pro/Leu) and 13% (Pro/Pro) in the patient group and 8.7% (Leu/Leu), 67.3% (Pro/Leu) and 24% (Pro/Pro) in the control group. The genotype and allele frequencies of GPx1 Pro198Leu did not differ between the patient group and the control group (P = 0.09 and P = 0.1, respectively). In conclusion, there is no correlation between idiopathic male infertility and the GPx1 codon Pro198Leu polymorphism. Further studies are needed to investigate other genetic factors that influence the development of idiopathic male infertility.     

Genome-wide screening of severe male factor infertile patients using BAC-array comparative genomic hybridization (CGH)

Male factor infertility is present in up to 50% of infertile couples, making it increasingly important in their treatment. Although most research into the genetics of male infertility has focused on the Y chromosome, male factor infertility may result from other genetic factors. We utilized the whole genome array comparative genomic hybridization (CGH) to identify novel genetic candidate associated with severely impaired spermatogenesis. We enrolled 37 patients with severe male factor infertility, defined as severe nonobstructive type oligozoospermia (≤5×10(6)/ml) or azoospermia, and 10 controls. Routine cytogenetic analyses, Yq microdeletion PCR test and whole genome bacterial artificial chromosome (BAC)-array CGH were performed. Array CGH results showed no specific gains or losses related to impaired spermatogenesis other than Yq microdeletions, and there were no novel candidate genetic abnormalities in the patients with severe male infertility. However, Yq microdeletions were detected in 10 patients. Three showed a deletion in the AZFb-c region and the other 7 had deletions in the AZFc region. Although we could not identify novel genetic regions specifically associated with male infertility, whole genome array CGH analysis with higher resolution including larger numbers of patients may be able to give an opportunity for identifying new genetic markers for male infertility.     

Génétique de l’infertilité chez l’homme, nouvelles approches

15% of couples worldwide present with reproduction difficulties related to infertility. To date, very few genetic causes have been associated with male or female infertility. The identification of single-gene mutations causing male infertility is not a field of intense research at the present time, although they are probably responsible for a large number of so-called idiopathic cases of infertility. Murine models were created several years ago by gene knock-out by genetic recombination: more than 200 genes have been shown to be responsible for isolated syndromic infertility. This is the case for genes controlling meiosis. The course of meiosis and the genes associated with this process have been largely characterized in yeasts. Mammalian homologues were recently cloned and knocked out in mice, demonstrating their essential roles during meiosis and gametogenesis. The gonadal phenotype of these mutant animals is similar to that of certain patients with unexplained infertility. The search for possible mutations in meiosis genes, genes that have been highly preserved during evolution, is currently underway. These murine models are very useful to study and dissect the various steps of normal and pathological gametogenesis in mammals. This progress should lead, in the near future, to more precise diagnosis and therefore informed genetic counselling in these infertile couples.     

Follicle stimulating hormone receptor G-29A, 919A>G, 2039A>G polymorphism and the risk of male infertility: a meta-analysis

Studies of the relationship between male infertility and polymorphisms in the regions of FSHR G-29A (rs1394205), 919A>G (Thr(307)Ala, rs6165) and 2039A>G (Asn(680)Ser, rs6166) have reported inconsistent results. To assess the association between them, a meta-analysis was conducted. PubMed and CBMdisc literature search were conducted to identify all eligible studies investigating such a relationship. The pooled ORs were performed for co-dominant model, dominant model and recessive model in FSHR G-29A, Thr(307)Ala and Asn(680)Ser respectively to assess the strength of association. A total of 1644 male infertility cases and 1748 controls were collected from seven case-control studies. In the overall analysis, no significant association between the three polymorphisms and risk of male infertility was observed. Stratified analysis showed that there were no significantly increased risks of azoospermia and oligoasthenoteratozoospermia (OAT) in any of the genetic models. This meta-analysis supports that FSHR G-29A, Thr(307)Ala and Asn(680)Ser polymorphisms may not be capable of causing male infertility susceptibility.