Microdeletions in the Y chromosome have been found at a much higher rate in infertile men than in fertile controls and the correlation found may still go up as improved genetic testing techniques for the Y chromosome are developed.

Much study has been focused upon the "azoospermia factor locus" (AZF), at Yq11. A specific partial deletion of AZFc called "gr/gr deletion" is significantly associated with male infertility among Caucasians in Europe and the Western Pacific region.

Additional genes associated with spermatogenesis in men and reduced fertility upon Y chromosome deletions include RBM, DAZ, SPGY, and TSPY.

Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a known aneugen (aneuploidy inducing agent). It is associated with increases in aneuploidy ranging from 1.5 to 3.0-fold. Other studies indicate factors such as alcohol consumption, occupational exposure to benzene, and exposure to the insecticides fenvalerate and carbaryl also increase aneuploidy.

The mechanism of mutation is not different for Y-chromosome microdeletion. However, the ability to repair it differs from other chromosomes. The human Y chromosome is passed directly from father to son, and is not protected against accumulating copying errors, whereas other chromosomes are error corrected by recombining genetic information from mother and father. This may leave natural selection as the primary repair mechanism for the Y chromosome.

Human trisomies compatible with live birth, other than Down syndrome (trisomy 21), are Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13). Complete trisomies of other chromosomes are usually not viable and represent a relatively frequent cause of miscarriage. Only in rare cases of a mosaicism, the presence of a normal cell line, in addition to the trisomic cell line, may support the development of a viable trisomy of the other chromosomes.

In a normal situation, all the cells in an individual will have 46 chromosomes with one being an X and one a Y or with two Xs. However, sometimes during this complicated early copying process (DNA replication and cell division), one chromosome can be lost. In 45,X/46,XY, most or all of the Y chromosome is lost in one of the newly created cells. All the cells then made from this cell will lack the Y chromosome. All the cells created from the cells that have not lost the Y chromosome will be XY. The 46,XY cells will continue to multiply at the same time as the 45,X cells multiply. The embryo, then the fetus and then the baby will have what is called a 45,X/46,XY constitution. This is called a

mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell.

There are many chromosomal variations that cause the 45,X/46,XY karyotype, including malformation (isodicentricism) of the Y chromosomes, deletions of Y chromosome or translocations of Y chromosome segments. These rearrangements of the Y chromosome can lead to partial expression of the SRY gene which may lead to abnormal genitals and testosterone levels.

As the syndrome is due to a chromosomal non-disjunction event, the recurrence risk is not high compared to the general population. There has been no evidence found that indicates non-disjunction occurs more often in a particular family.

Kleefstra syndrome affects males and females equally and approximately, 75% of all documented cases are caused by Eu-HMTase1 disruptions while only 25% are caused by 9q34.3 deletions. There are no statistics on the effect the disease has on life expectancy due to the lack of information available.

Patients have an essentially normal life expectancy but require regular medical follow-up.

This syndrome, evenly spread in all ethnic groups, has a prevalence of 1-2 subjects per every 1000 males in the general population. 3.1% of infertile males have Klinefelter syndrome. The syndrome is also the main cause of male hypogonadism.

According to 2008 meta-analysis, the prevalence of the syndrome has increased over the past decades; however, this does not appear to be related to increased age of the mother at conception, as no increase was observed in the rates of other trisomies of sex chromosomes (XXX and XYY). The National Institutes of Health; however, state that older mothers might have a slightly increased risk.

Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular disorder.

At puberty, most affected individuals require treatment with the male sex hormone testosterone to induce development of male secondary sex characteristics such as facial hair and deepening of the voice (masculinization). Hormone treatment can also help prevent breast enlargement (gynecomastia). Adults with this disorder are usually shorter than average for males and are unable to have children (infertile).

Children with XXY differ little from other children. Although they can face problems during adolescence, often emotional and behavioral, and difficulties at school, most of them can achieve full independence from their families in adulthood. Most can lead a normal, healthy life.

The results of a study carried out on 87 Australian adults with the syndrome shows that those who have had a diagnosis and appropriate treatment from a very young age had a significant benefit with respect to those who had been diagnosed in adulthood.

There is research suggesting Klinefelter syndrome substantially decreases life expectancy among affected individuals, though the evidence is not definitive. A 1985 publication identified a greater mortality mainly due to diseases of the aortic valve, development of tumors and possible subarachnoid hemorrhages, reducing life expectancy by about 5 years. Later studies have reduced this estimated reduction to an average of 2.1 years. These results are still questioned data, are not absolute, and will need further testing.

The cause of 48, XXXY can be from non-disjunction in the paternal sperm or non-disjunction in the maternal oocyte. The most likely scenario for the existence of this aneuploidy is that each parent (maternal and paternal) equally contributed to it, by the mother giving an XX and the father giving an XY.

In the case where the sperm is the genetic cause of 48, XXXY syndrome, the sperm would have to contain two X chromosomes and one Y chromosome. This would be caused by two non-disjunction events in spermatogenesis, both meosis I and meosis II. The duplicated X chromosome in the sperm would have to fail to separate in both meosis I and meosis II for a sperm as well as the X and Y chromosomes would have to be in the same sperm. Then the XXY sperm would fertilize a normal oocyte to make a XXXY zygote.

In the case where the oocyte is the genetic cause of 48, XXXY syndrome the oocyte would contain three X chromosome. This would be caused by two non-disjunction events during oogenesis. In meosis I both sets of duplicated X chromosomes would have to be not separated. Then in meosis II one set of X chromosomes would have to not separate and the other set would separate resulting in one oocyte with three X chromosomes. A normal sperm containing a Y chromosome would have to fertilize the XXX oocyte to make a XXXY zygote.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a rare disorder of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. This is called a mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell.

The clinical manifestations are highly variable, ranging from partial virilisation and ambiguous genitalia at birth, to patients with a completely male or female gonads. Most individuals with this karyotype have apparently normal male genitalia, and a minority with female genitalia, with a significant number of individuals showing genital abnormalities or intersex characteristics. A significantly higher than normal number of other developmental abnormalities are also found in individuals with X0/XY mosaicism. Psychomotor development is normal.

The condition 48,XXYY is not inherited; it usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. In 48,XXYY syndrome, the extra sex chromosomes almost always come from a sperm cell. Nondisjunction may cause a sperm cell to gain two extra sex chromosomes, resulting in a sperm cell with three sex chromosomes (one X and two Y chromosomes). If that sperm cell fertilizes a normal egg cell with one X chromosome, the resulting child will have two X chromosomes and two Y chromosomes in each of the body's cells.

In a small percentage of cases, 48,XXYY syndrome results from nondisjunction of the sex chromosomes in a 46,XY embryo very soon after fertilization has occurred. This means that an normal sperm cell with one Y chromosome fertilized a normal egg cell with one X chromosome, but right after fertilization nondisjunction of the sex chromosomes caused the embryo to gain two extra sex chromosomes, resulting in a 48,XXYY embryo.

Lujan–Fryns syndrome is a rare X-linked dominant syndrome, and is therefore more common in males than females. Its prevalence within the general population has not yet been determined.

XX male syndrome is a rare congenital condition where an individual with a female genotype has phenotypically male characteristics that can vary between cases. In 90% of these individuals the syndrome is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, and results in the X chromosome containing the SRY gene, as opposed to the Y chromosome where it is normally found. When the X with the SRY gene combines with a normal X from the mother during fertilization, the result is an XX male. Less common are SRY-negative XX males which can be caused by a mutation in an autosomal or X chromosomal gene. The masculinization of XX males is variable.

This syndrome is diagnosed through various detection methods and occurs in approximately 1:20 000 newborn males, making it less common than Klinefelter syndrome. Treatment is medically unnecessary, although some individuals choose to undergo treatments to make them appear more male or female. It is also called de la Chapelle syndrome, for Albert de la Chapelle, who characterized it in 1972.

Individuals with CAIS are raised as females. They are born phenotypically female and almost always have a heterosexual female gender identity; the incidence of homosexuality in women with CAIS is thought to be less than unaffected women. However, at least two case studies have reported male gender identity in individuals with CAIS.

Nuclear receptor subfamily 5 group A member 1 (NR5A1), also known as SF1 or Ad4BP (MIM 184757), is located on the long arm of chromosome 9 (9q33.3). The NR5A1 is an orphan nuclear receptor that was first identified following the search for a common regulator of the cytochrome P450 steroid hydroxylase enzyme family. This receptor is a pivotal transcriptional regulator of an array of genes involved in reproduction, steroidogenesis and male sexual differentiation and also plays a crucial role in adrenal gland formation in both sexes. NR5A1 regulates the mullerian inhibitory substance by binding to a conserved upstream regulatory element and directly participates in the process of mammalian sex determination through mullerian duct regression. Targeted disruption of NR5A1 (Ftzf1) in mice results in gonadal and adrenal agenesis, persistence of Mullerian structures and abnormalities of the hypothalamus and pituitary gonadotropes. Heterozygous animals demonstrate a milder phenotype including an impaired adrenal stress response and reduced testicular size. In humans, NR5A1 mutations were first described in patients with 46, XY karyotype and disorders of sex development (DSD), Mullerian structures and primary adrenal failure (MIM 612965). After that, heterozygous NR5A1 mutations were described in seven patients showing 46, XY karyotype and ambiguous genitalia, gonadal dysgenesis, but no adrenal insufficiency. Since then, studies have confirmed that mutations in NR5A1 in patients with 46, XY karyotype cause severe underandrogenisation, but no adrenal insufficiency, establishing dynamic and dosage-dependent actions for NR5A1. Subsequent studies revealed that NR5A1 heterozygous mutations cause primary ovarian insufficiency (MIM 612964).

Due to its recent discovery, there are currently no existing treatments for Kleefstra syndrome.

About 10–15% of human couples are infertile, unable to conceive. In approximately in half of these cases, the underlying cause is related to the male. The underlying causative factors in the male infertility can be attributed to environmental toxins, systemic disorders such as, hypothalamic–pituitary disease, testicular cancers and germ-cell aplasia. Genetic factors including aneuploidies and single-gene mutations are also contributed to the male infertility. Patients suffering from nonobstructive azoospermia or oligozoospermia show microdeletions in the long arm of the Y chromosome and/or chromosomal abnormalities, each with the respective frequency of 9.7% and 13%. A large percentage of human male infertility is estimated to be caused by mutations in genes involved in primary or secondary spermatogenesis and sperm quality and function. Single-gene defects are the focus of most research carried out in this field.

NR5A1 mutations are associated with male infertility, suggesting the possibility that these mutations cause the infertility. However, it is possible that these mutations individually have no major effect and only contribute to the male infertility by collaboration with other contributors such as environmental factors and other genomics variants. Vice versa, existence of the other alleles could reduce the phenotypic effects of impaired NR5A1 proteins and attenuate the expression of abnormal phenotypes and manifest male infertility solely.

The degree to which individuals with XX male syndrome develop the male phenotype is variable, even among SRY-positive individuals. A completely male phenotype usually develops in the presence of the SRY gene but, in some cases, the presence of the SRY gene can result in internal and/or external genitalia ambiguities. Normal XX females undergo X inactivation during which one copy of the X chromosome is silenced. It is thought that X inactivation in XX males may account for the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. The X chromosome with the SRY gene is preferentially chosen to be the active X chromosome 90% of the time, which is why a complete male phenotype is often seen in SRY-positive XX males. In the remaining 10%, X inactivation spreads to include a portion of the SRY gene, resulting in incomplete masculinization.

Masculinization of SRY-negative XX males is dependent upon which genes have mutations and at what point in development these mutations occur.

The true prevalence of PMS has not been determined. More than 1200 people have been identified worldwide according the Phelan-McDermid Syndrome Foundation. However, it is believed to be underdiagnosed due to inadequate genetic testing and lack of specific clinical features. It is known to occur with equal frequency in males and females. Studies using chromosomal microarray for diagnosis indicate that at least 0.5% of cases of ASD can be explained by mutations or deletions in the "SHANK3" gene. In addition when ASD is associated with ID, "SHANK3" mutations or deletions have been found in up to 2% of individuals.

47,XYY is not inherited, but usually occurs as a random event during the formation of sperm cells. An incident in chromosome separation during anaphase II (of meiosis II) called nondisjunction can result in sperm cells with an extra copy of the Y-chromosome. If one of these atypical sperm cells contributes to the genetic makeup of a child, the child will have an extra Y-chromosome in each of the body's cells.

In some cases, the addition of an extra Y-chromosome results from nondisjunction during cell division during a post-zygotic mitosis in early embryonic development. This can produce 46,XY/47,XYY mosaics.

The syndrome primarily affects young males. Preliminary studies suggest that prevalence may be 1.8 per 10,000 live male births. 50% of those affected do not live beyond 25 years of age, with deaths attributed to the impaired immune function.