Germline mosaicism

Last updated

Germline mosaicism, also called gonadal mosaicism, is a type of genetic mosaicism where more than one set of genetic information is found specifically within the gamete cells; conversely, somatic mosaicism is a type of genetic mosaicism found in somatic cells. Germline mosaicism can be present at the same time as somatic mosaicism or individually, depending on when the conditions occur. Pure germline mosaicism refers to mosaicism found exclusively in the gametes and not in any somatic cells. Germline mosaicism can be caused either by a mutation that occurs after conception, [1] [2] or by epigenetic regulation, [3] alterations to DNA such as methylation that do not involve changes in the DNA coding sequence.

Contents

A mutation in an allele acquired by a somatic cell early in its development can be passed on to its daughter cells, including those that later specialize to gametes. With such mutation within the gamete cells, a pair of medically typical individuals may have repeated succession of children who suffer from certain genetic disorders such as Duchenne muscular dystrophy and osteogenesis imperfecta because of germline mosaicism. It is possible for parents unaffected by germline mutations to produce an offspring with an autosomal dominant (AD) disorder due to a random new mutation within one’s gamete cells known as sporadic mutation; however, if these parents produce more than one child with an AD disorder, germline mosaicism is more likely the cause than a sporadic mutation. [4] [ unreliable source? ] In the first documented case of its kind, two offspring of a French woman who had no phenotypic expression of the AD disorder hypertrophic cardiomyopathy, inherited the disease. [5]

Inheritance

Germline mosaicism disorders are usually inherited in a pattern that suggests that the condition is dominant in either or both of the parents. That said, diverging from Mendelian gene inheritance patterns, a parent with a recessive allele can produce offspring expressing the phenotype as dominant through germline mosaicism. A situation may also arise in which the parents have milder phenotypic expression of a mutation yet produce offspring with more expressive phenotypic variance and a more frequent sibling recurrences of the mutation. [6] [7] [8]

Diseases caused by germline mosaicism can be difficult to diagnose as genetically-inherited because the mutant alleles are not likely to be present in the somatic cells. Somatic cells are more commonly used for genetic analysis because they are easier to obtain than gametes. If the disease is a result of pure germline mosaicism, then the disease causing mutant allele would never be present in the somatic cells. This is a source of uncertainty for genetic counselling. An individual may still be a carrier for a certain disease even if the disease causing mutant allele is not present in the cells that were analyzed because the causative mutation could still exist in some of the individual's gametes. [9]

Germline mosaicism may contribute to the inheritance of many genetic conditions. Conditions that are inherited by means of germline mosaicism are often mistaken as being the result of de novo mutations. Various diseases are now being re-examined for presence of mutant alleles in the germline of the parents in order to further our understanding of how they can be passed on. [10] The frequency of germline mosaicism is not known due to the sporadic nature of the mutations causing it and the difficulty in obtaining the gametes that must be tested to diagnose it.

Diagnosis

Autosomal dominant or X-linked familial disorders often prompt prenatal testing for germline mosaicism. This diagnosis may involve minimally invasive procedures, such as blood sampling or amniotic fluid sampling. [9] [11] [12] [13] [14] Collected samples can be sequenced via common DNA testing methods, such as Sanger Sequencing, MLPA, or Southern Blot analysis, to look for variations on relevant genes connected to the disorder. [14] [15]

Recurrence rate

The recurrence rate of conditions caused by germline mosaicism varies greatly between subjects. Recurrence is proportional to the number of gamete cells that carry the particular mutation with the condition. If the mutation occurred earlier on in the development of the gamete cells, then the recurrence rate would be higher because a greater number of cells would carry the mutant allele. [11]

Case studies

A Moroccan family consisting of two healthy unrelated parents and three offspring—including two with Noonan syndrome, a rare autosomal dominant disorder with varying expression and genetic heterogeneity—underwent genetic testing revealing that both of the siblings with NS share the same PTPN11 haplotype from both parents, while a distinct paternal and maternal haplotype was inherited by the unaffected sibling. [16] In the paper Germline and somatic mosaicism in transgenic mice published in 1986, Thomas M.Wilkie, Ralph L.Brinster, and Richard D.Palmiter analyzed a germline mosaicism experiment done on 262 transgenic mice and concluded that 30% of founder transgenic mice are mosaic in the germline. [17]

Notes

  1. ↑ Orva, Rosa; Orva, David (April 1998). "Germ line Mosaicism". Human Genetics. 102 (4): 381–6. doi:10.1007/s004390050708. PMID   9600231. S2CID   22007840.
  2. ↑ Nussbuam, McInnes, Willard. Genetics In Medicine. Elsevier. pp. 123–125. ISBN   978-1-4377-0696-3.
  3. ↑ Laurentino, S.; Beygo, J.; Nordhoff, V.; Kliesch, S.; Wistuba, J.; Borgmann, J.; Buiting, K.; Horsthemke, B.; Gromoll, J. (21 October 2014). "Epigenetic germline mosaicism in infertile men". Human Molecular Genetics. 24 (5): 1295–1304. doi: 10.1093/hmg/ddu540 . PMID   25336341.
  4. ↑ "Germline Mosaicism". John P. Hussman Institute for Human Genomics module.
  5. ↑ Forissier, J. F.; Richard, P.; Briault, S.; Ledeuil, C.; Dubourg, O.; Charbonnier, B.; Carrier, L.; Moraine, C.; Bonne, G.; Komajda, M.; Schwartz, K.; Hainque, B. (2000). "First description of germline mosaicism in familial hypertrophic cardiomyopathy". Journal of Medical Genetics. 37 (2): 132–134. doi:10.1136/jmg.37.2.132. PMC   1734529 . PMID   10662815.
  6. ↑ Nancy B. Spinner; Biesecker, Leslie G. (2013). "A genomic view of mosaicism and human disease". Nature Reviews Genetics. 14 (5): 307–320. doi:10.1038/nrg3424. ISSN   1471-0064. PMID   23594909. S2CID   4494815.
  7. ↑ Edwards, J. H. (1989-01-01). "Familiarity, recessivity and germline mosaicism". Annals of Human Genetics. 53 (1): 33–47. doi:10.1111/j.1469-1809.1989.tb01120.x. PMID   2658737. S2CID   28036553.
  8. ↑ Zlotogora, Joël (1998-04-01). "Germ line mosaicism". Human Genetics. 102 (4): 381–386. doi:10.1007/s004390050708. ISSN   1432-1203. PMID   9600231. S2CID   22007840.
  9. 1 2 Chi Hyan, Cho; et al. (2015). "A Case Report of a Fetus with Mosaic Autosomal Variegated Aneuploidies and Literature Review". Annals of Clinical & Laboratory Science. 45 (1): 106–109. PMID   25696020 . Retrieved December 3, 2015.
  10. ↑ Armaroli, Annarita; Trabanelli, Cecilia; Scotton, Chiara; Venturoli, Anna; Selvatici, Rita; Brisca, Giacomo; Merlini, Luciano; Bruno, Claudio; Ferlini, Alessandra (2015-09-01). "Paternal germline mosaicism in collagen VI related myopathies". European Journal of Paediatric Neurology. 19 (5): 533–536. doi:10.1016/j.ejpn.2015.04.002. hdl: 11392/2330840 . PMID   25978941.
  11. 1 2 Edwards, J. H. (1989). "Familiarity, recessivity and germline mosaicism". Annals of Human Genetics. 53 (1): 33–47. doi:10.1111/j.1469-1809.1989.tb01120.x. ISSN   1469-1809. PMID   2658737. S2CID   28036553.
  12. ↑ Mari, F.; Caselli, R.; Russo, S.; Cogliati, F.; Ariani, F.; Longo, I.; Bruttini, M.; Meloni, I.; Pescucci, C. (2005). "Germline mosaicism in Rett syndrome identified by prenatal diagnosis". Clinical Genetics. 67 (3): 258–260. doi:10.1111/j.1399-0004.2005.00397.x. hdl: 2434/13970 . ISSN   1399-0004. PMID   15691364. S2CID   29782253.
  13. ↑ Betsalel, Ofir T.; van de Kamp, Jiddeke M.; Martínez-Muñoz, Cristina; Rosenberg, Efraim H.; de Brouwer, Arjan P. M.; Pouwels, Petra J. W.; van der Knaap, Marjo S.; Mancini, Grazia M. S.; Jakobs, Cornelis (2008-07-01). "Detection of low-level somatic and germline mosaicism by denaturing high-performance liquid chromatography in a EURO-MRX family with SLC6A8 deficiency". Neurogenetics. 9 (3): 183–190. doi:10.1007/s10048-008-0125-5. ISSN   1364-6753. PMID   18350323. S2CID   16211597.
  14. 1 2 Wilkie, Andrew O. M.; Goriely, Anne (September 2019). "Gonadal mosaicism and non‐invasive prenatal diagnosis for 'reassurance' in sporadic paternal age effect (PAE) disorders". Prenatal Diagnosis. 37 (9): 946–948. doi:10.1002/pd.5108. ISSN   0197-3851. PMC   5638092 . PMID   28686291.
  15. ↑ Sgambati, M. T.; Stolle, C.; Choyke, P. L.; Walther, M. M.; Zbar, B.; Linehan, W. M.; Glenn, G. M. (2000-01-01). "Mosaicism in von Hippel–Lindau Disease: Lessons from Kindreds with Germline Mutations Identified in Offspring with Mosaic Parents". The American Journal of Human Genetics. 66 (1): 84–91. doi:10.1086/302726. ISSN   0002-9297. PMC   1288351 . PMID   10631138.
  16. ↑ Elalaoui SC, Kraoua L, Liger C, Ratbi I, CaveH, Sefiani A. 2010. Germinal mosaicism in Noonan syndrome: A family with two affected siblings of normal parents. Am J Med Genet Part A 152A:2850–2853
  17. ↑ Thomas M. Wilkie, Ralph L. Brinster, Richard D. Palmiter. 1986. Germline and somatic mosaicism in transgenic mice, Developmental Biology, Volume 118, Issue 1, pp. 9-18. ISSN 0012-1606.

Related Research Articles

<span class="mw-page-title-main">Autosome</span> Any chromosome other than a sex chromosome

An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal pairs, which may have different structures. The DNA in autosomes is collectively known as atDNA or auDNA.

<span class="mw-page-title-main">Mutation</span> Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

<span class="mw-page-title-main">Tay–Sachs disease</span> Human medical condition

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur later in childhood, adolescence, or adulthood. These forms tend to be less severe, but the juvenile form typically results in death by age 15.

In cellular biology, a somatic cell, or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Somatic cells compose the body of an organism and divide through mitosis.

Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be separated onto different chromatids during chromosomal crossover, and are therefore said to be more linked than markers that are far apart. In other words, the nearer two genes are on a chromosome, the lower the chance of recombination between them, and the more likely they are to be inherited together. Markers on different chromosomes are perfectly unlinked, although the penetrance of potentially deleterious alleles may be influenced by the presence of other alleles, and these other alleles may be located on other chromosomes than that on which a particular potentially deleterious allele is located.

<span class="mw-page-title-main">Preimplantation genetic diagnosis</span> Genetic profiling of embryos prior to implantation

Preimplantation genetic diagnosis is the genetic profiling of embryos prior to implantation, and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal diagnosis. When used to screen for a specific genetic disease, its main advantage is that it avoids selective abortion, as the method makes it highly likely that the baby will be free of the disease under consideration. PGD thus is an adjunct to assisted reproductive technology, and requires in vitro fertilization (IVF) to obtain oocytes or embryos for evaluation. Embryos are generally obtained through blastomere or blastocyst biopsy. The latter technique has proved to be less deleterious for the embryo, therefore it is advisable to perform the biopsy around day 5 or 6 of development.

<span class="mw-page-title-main">Mosaic (genetics)</span> Condition in multi-cellular organisms

Mosaicism or genetic mosaicism is a condition in which a multicellular organism possesses more than one genetic line as the result of genetic mutation. This means that various genetic lines resulted from a single fertilized egg. Mosaicism is one of several possible causes of chimerism, wherein a single organism is composed of cells with more than one distinct genotype.

<span class="mw-page-title-main">Darier's disease</span> Medical condition

Darier's disease (DAR) is a rare, inherited skin disorder that presents with multiple greasy, crusting, thick brown bumps that merge into patches. It is an autosomal dominant disorder discovered by French dermatologist Ferdinand-Jean Darier.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

Heteroplasmy is the presence of more than one type of organellar genome within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected.

<span class="mw-page-title-main">Non-Mendelian inheritance</span> Type of pattern of inheritance

Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent contributes one of two possible alleles for a trait. If the genotypes of both parents in a genetic cross are known, Mendel's laws can be used to determine the distribution of phenotypes expected for the population of offspring. There are several situations in which the proportions of phenotypes observed in the progeny do not match the predicted values.

Genetics, a discipline of biology, is the science of heredity and variation in living organisms.

<span class="mw-page-title-main">Schwannomatosis</span> Rare genetic disorder

Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. The exact frequency of schwannomatosis cases is unknown, although some populations have noted frequencies as few as 1 case per 1.7 million people.

A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.

An obligate carrier is an individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive and X-linked recessive manner.

Diffuse infantile fibromatosis is a rare condition affecting infants during the first three years of life. This condition is a multicentric infiltration of muscle fibers with fibroblasts resembling those seen in aponeurotic fibromas, presenting as lesions and tumors confined usually to the muscles of the arms, neck, and shoulder area Diffuse infantile fibromatosis is characterized by fast growing benign tumors. This disorder is known to be caused by mutations in germline variants, PDGFRB and NOTCH3, which may be generationally-inherited through autosomal dominant and recessive traits. Although diffuse infantile fibromatosis is classified as benign, it can still lead to life-threatening complications and damage other organs.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

Human germline engineering is the process by which the genome of an individual is edited in such a way that the change is heritable. This is achieved by altering the genes of the germ cells, which then mature into genetically modified eggs and sperm. For safety, ethical, and social reasons, there is broad agreement among the scientific community and the public that germline editing for reproduction is a red line that should not be crossed at this point in time. There are differing public sentiments, however, on whether it may be performed in the future depending on whether the intent would be therapeutic or non-therapeutic.

Human somatic variations are somatic mutations both at early stages of development and in adult cells. These variations can lead either to pathogenic phenotypes or not, even if their function in healthy conditions is not completely clear yet.

A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutations, which can be passed on to the descendants of an organism, somatic mutations are not usually transmitted to descendants. This distinction is blurred in plants, which lack a dedicated germline, and in those animals that can reproduce asexually through mechanisms such as budding, as in members of the cnidarian genus Hydra.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.