Genetics of infertility#Small supernumerary marker chromosomes and infertility
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 with 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.{{cite journal|last1=Matzuk|first1=Martin M|last2=Lamb|first2=Dolores J|title=The biology of infertility: research advances and clinical challenges|journal=Nature Medicine|date=6 November 2008|volume=14|issue=11|pages=1197–1213|doi=10.1038/nm.f.1895|pmc=3786590|pmid=18989307}}{{cite journal|last1=Skakkebæk|first1=N.E.|last2=Giwercman|first2=A.|last3=de Kretser|first3=D.|title=Pathogenesis and management of male infertility|journal=The Lancet|date=June 1994|volume=343|issue=8911|pages=1473–1479|doi=10.1016/S0140-6736(94)92586-0|pmid=7911182 |s2cid=206007969 }}
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.{{cite web | url=https://geneswellness.com/genetics-and-infertility/ | title=Genetics and Infertility: From Heartbreak to Hope | work=GenesWellness | date=January 20, 2024 | accessdate=February 15, 2024| author=Dr. Sumeet, K}} 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.
NR5A1 new roles in fertility and infertility
Recently, NR5A1 mutations have been related to human male infertility (MIM 613957). These findings substantially increase the number of NR5A1 mutations reported in humans and show that mutations in NR5A1 can be found in patients with a wide range of phenotypic features, ranging from 46,XY sex reversal with primary adrenal failure to male infertility. For the first time, Bashamboo et al. (2010) conducted a study on the nonobstructive infertile men (a non-Caucasian mixed ancestry n = 315), which resulted in the report of all missense mutations in the NR5A1 gene with 4% frequency. Functional studies of the missense mutations revealed impaired transcriptional activation of NR5A1-responsive target genes. Subsequently, three missense mutations were identified as associated with and most likely the cause of the male infertility, according to computational analyses.{{cite journal|last1=Röpke|first1=Albrecht|last2=Tewes|first2=Ann-Christin|last3=Gromoll|first3=Jörg|last4=Kliesch|first4=Sabine|last5=Wieacker|first5=Peter|last6=Tüttelmann|first6=Frank|title=Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males|journal=European Journal of Human Genetics|date=9 January 2013|volume=21|issue=9|pages=1012–1015|doi=10.1038/ejhg.2012.290|pmid=23299922|pmc=3746266}} The study indicated that the mutation frequency is below 1% (Caucasian German origin, n = 488). In another study the coding sequence of NR5A1 has been analysed in a cohort of 90 well-characterised idiopathic Iranian azoospermic infertile men versus 112 fertile men.{{cite journal|last1=Zare-Abdollahi|first1=D.|last2=Safari|first2=S.|last3=Mirfakhraie|first3=R.|last4=Movafagh|first4=A.|last5=Bastami|first5=M.|last6=Azimzadeh|first6=P.|last7=Salsabili|first7=N.|last8=Ebrahimizadeh|first8=W.|last9=Salami|first9=S.|last10=Omrani|first10=M. D.|title=Mutational screening of the NR5A1 in azoospermia|journal=Andrologia|date=May 2015|volume=47|issue=4|pages=395–401|doi=10.1111/and.12274|pmid=24750329 |s2cid=22957760 |doi-access=free}} Heterozygous NR5A1 mutations were found in 2 of 90 (2.2%) of cases. These two patients harboured missense mutations within the hinge region (p.P97T) and ligand-binding domain (p.E237K) of the NR5A1 protein.
=Small supernumerary marker chromosomes and infertility=
{{main|Small supernumerary marker chromosome#sSMC-associated infertility}}
Small supernumerary marker chromosome (sSMCs) are extra chromosomes consisting of parts of virtually any other chromosome(s). By definition, they are smaller than one of the smaller chromosomes, chromosome 20. sSMCs typically develop in individuals as a result of abnormal chromosomal events occurring in one of their parent's eggs, sperms, or zygotes but in less common cases are directly inherited from a parent carrier of the sSMC.{{cite journal | vauthors = Matsubara K, Yanagida K, Nagai T, Kagami M, Fukami M | title = De Novo Small Supernumerary Marker Chromosomes Arising From Partial Trisomy Rescue | journal = Frontiers in Genetics | volume = 11 | issue = | pages = 132 | date = 2020 | pmid = 32174976 | pmc = 7056893 | doi = 10.3389/fgene.2020.00132 | url = | doi-access = free }} sSMCs occur in 0.125% of all infertility cases,{{cite journal | vauthors = Liehr T, Weise A | title = Frequency of small supernumerary marker chromosomes in prenatal, newborn, developmentally retarded and infertility diagnostics | journal = International Journal of Molecular Medicine | volume = 19 | issue = 5 | pages = 719–31 | date = May 2007 | pmid = 17390076 | doi = | url = }} are 7.5-fold more common in men, and in women are often associated with ovarian failure.{{cite journal | vauthors = Armanet N, Tosca L, Brisset S, Liehr T, Tachdjian G | title = Small Supernumerary Marker Chromosomes in Human Infertility | journal = Cytogenetic and Genome Research | volume = 146 | issue = 2 | pages = 100–8 | date = 2015 | pmid = 26398339 | doi = 10.1159/000438718 | url = | doi-access = free }} The sSMCs associated with infertility can consist of parts of virtually any other chromosome. While only a small percentage of these sSMCs have had their genetic material defined, those that have include sSMCs containing: a) band 11.1 from the short arm of chromosome 15 (notated as (15)q11.1)(this sSMC is associated with premature ovarian failure); b) band ll.2 from the short arm of chromosome 13 (notated as (13)q11.2)(this sSMC is associated with oligoasthenoteratozoospermia, i.e. oligozoospermia [low sperm count], teratozoospermia [presence of sperm with abnormal shapes], and asthenozoospermia [sperm with reduced motility]); c) band 11 from the short arm of chromosome 14 (notated as (14)q11.1)(this sCMC is associated with otherwise uncharacterized infertility; and d) band 11 on the short arm of chromosome 22 notated as (22)q11)(this sSMC is associated with repeated abortions).{{cite journal | vauthors = Sun M, Zhang H, Xi Q, Li L, Hu X, Zhang H, Liu R | title = Molecular characterization of small supernumerary marker chromosomes derived from chromosome 14/22 detected in adult women with fertility problems: Three case reports and literature review | journal = Medicine | volume = 99 | issue = 40 | pages = e22532 | date = October 2020 | pmid = 33019458 | pmc = 7535553 | doi = 10.1097/MD.0000000000022532 | url = }}