What is number of chromosomes in human ?
Human Chromosome
Human Chromosomes
Human chromosomes were probably first observed in cancer cells by Arnold in 1879. Hansemann in 1881 and Flemming in 1898 attempted to count the number in serial sections of mitotic cells producing crude estimates of approximately 24. Quite different results were produced in 1912 by de Winiwarter. He was probably the first to study gonadal material and found 47 chromosomes in testis and 48 in ovary. He concluded that humans, like the locust, had an XX female/X male sex-determining mechanism. Painter in 1923 repeated this work on sections of testis material, in which he detected the small Y chromosome which de Winiwarter had apparently missed. He concluded that 48 and not 47 was the correct number for humans of both sexes, but mentioned in his publication that in the clearest mitotic figures he could only count 46.
Introduction
Thomas Liehr, in Benign & Pathological Chromosomal Imbalances, 2014
Human chromosomes were first visualized in a microscope in the late 1870s [Arnold, 1879] and were named in 1888 by Heinrich Wilhelm Waldeyer by combining the words chroma (Greek χρ
ω˜μα, meaning color) and soma (Greek σω˜μα, meaning body) [Waldeyer, 1888]. Still, it was another 68 years before the correct modal chromosome number in humans was determined to be 46 [Tijo and Levan, 1956]. Notably, this particular finding was the starting point of the discipline “human cytogenetics,” which deals with the numerical and structural analysis of human chromosomes. Since that time in 1956, cytogenetics has played a crucial role in pre- and postnatal, as well as tumor cytogenetic diagnostics and research.
Down Syndrome
Thomas Liehr, in Benign & Pathological Chromosomal Imbalances, 2014
Human chromosomes were first visualized in a microscope in the late 1870s [Arnold, 1879] and were named in 1888 by Heinrich Wilhelm Waldeyer by combining the words chroma (Greek χρ
ω˜μα, meaning color) and soma (Greek σω˜μα, meaning body) [Waldeyer, 1888]. Still, it was another 68 years before the correct modal chromosome number in humans was determined to be 46 [Tijo and Levan, 1956]. Notably, this particular finding was the starting point of the discipline “human cytogenetics,” which deals with the numerical and structural analysis of human chromosomes. Since that time in 1956, cytogenetics has played a crucial role in pre- and postnatal, as well as tumor cytogenetic diagnostics and research.
Down Syndrome
A.B. Bowman, ... K.L. Summar, in Neural Circuit Development and Function in the Brain, 2013Trisomy of human chromosome 21 is the genetic basis of Down syndrome (DS). DS is a prototypical neurodevelopmental disorder associated with a spectrum of developmental disabilities. Triplication of an entire human chromosome has made basic research into the underlying molecular genetics, cellular biology, and neuropathology very challenging. However, advances have been made utilizing animal models of DS. These have allowed the identification of critical chromosomal regions and specific genes that underlie neurological and nonneurological aspects of DS. Such findings are expected to culminate in novel therapies that will ameliorate the impaired cognition and neurodegeneration seen in many individuals with DS.
Keywords: Alzheimer disease; Aneuploidy; Autism; Chromosomal engineering; Developmental delay; Intellectual disabilities; Mouse model; Neurodegeneration; Neurodevelopment; Neurogenesis; Trisomy 21Hematological CancersTom Brody Ph.D., in Clinical Trials (Second Edition), 2016a IntroductionThe human chromosomes are numbered 1–22, with two additional chromosomes called X and Y. Chromosomes 1–22 occur as two copies in every somatic cell. The X chromosome occurs as two copies in every female somatic cell, but only once in every male somatic cell. The Y chromosome occurs only once in every male somatic cell. Thus, the sex chromosomes in males are XY, and the sex chromosomes in females are XX.
Altogether, human somatic cells have 46 chromosomes (207). During mitosis, the genome condenses to form chromosomes that can be seen using a light microscope. The appearance of these chromosomes is called the karyotype.
Keywords: Alzheimer disease; Aneuploidy; Autism; Chromosomal engineering; Developmental delay; Intellectual disabilities; Mouse model; Neurodegeneration; Neurodevelopment; Neurogenesis; Trisomy 21Hematological CancersTom Brody Ph.D., in Clinical Trials (Second Edition), 2016a IntroductionThe human chromosomes are numbered 1–22, with two additional chromosomes called X and Y. Chromosomes 1–22 occur as two copies in every somatic cell. The X chromosome occurs as two copies in every female somatic cell, but only once in every male somatic cell. The Y chromosome occurs only once in every male somatic cell. Thus, the sex chromosomes in males are XY, and the sex chromosomes in females are XX.
Altogether, human somatic cells have 46 chromosomes (207). During mitosis, the genome condenses to form chromosomes that can be seen using a light microscope. The appearance of these chromosomes is called the karyotype.
In a point in the cell cycle, that is, during metaphase, each of the chromosomes can be seen to have two arms, the p arm and the q arm. The letter p refers to the short arm, while q refers to the long arm. Within each arm, numbers are assigned to large areas called regions, and another set of numbers is used to refer to bands within the regions. Numbering starts from the centromere, and increases as one moves towards the tip of each arm (208).
To provide an example, the term “14q32” refers to the second band in the third region of the q arm of chromosome 14 (209). (It is not the case that the number 32 is read as thirty-two. Instead, it is read as three-two.) Another example is as follows. The breast cancer gene BRCA1 is located at 17q21.31. This means that the gene is located on the q arm of chromosome 17, in region 2. Within region 2, the gene is located in band 1. Collectively, this may be called, “band two, one.” Within band 21, the gene resides in sub-band 31. Regarding the number 31, the 3 refers to a sub-band, and the number 1 refers to a sub-band within sub-band 3 (210).
Molecular endocrinology and endocrine geneticsRam K. Menon MD, ... Constantine A. Stratakis MD, D(med)Sci, in Pediatric Endocrinology (Fourth Edition), 2014Isolation and digestion of DNA and southern blottingThe human chromosome comprises a long double-stranded helical molecule of DNA associated with different nuclear proteins.3,4 As DNA forms the starting point of the synthesis of all the protein molecules in the body, molecular techniques using DNA have proven to be crucial in the development of diagnostic tools to analyze endocrine diseases. DNA can be isolated from any human tissue, including circulating white blood cells. About 200 µg of DNA can be obtained from 10 to 20 mL of whole blood with the efficiency of DNA extraction being dependent on the technique used and the method of anticoagulation employed. The extracted DNA can be stored almost indefinitely at an appropriate temperature.
Furthermore, lymphocytes can be transformed with the Epstein-Barr virus (and other means) to propagate indefinitely in cell culture as “immortal” cell lines, thus providing a renewable source of DNA. For performing molecular genetic studies, lymphoid lines are routinely the tissue of choice, because a renewable source of DNA obviates the need to obtain further blood from the family. Fibroblast-derived cultures can also serve as a permanent source of DNA or RNA (once transformed), but they have to be derived from surgical specimens or a biopsy. It should be noted that, because the expression of many genes is tissue specific, immortalized lymphoid or fibroblastoid cell lines cannot be used to anlyze the abundance or composition of messenger RNA (mRNA) for a specific gene. Hence, studies involving mRNA necessitate the analysis of the tissue(s) expressing the gene as outlined in the section on “RNA Analysis” that begins on page 13.
DNA is present in extremely large molecules; the smallest chromosome (chromosome 22) has about 50 million base pairs and the entire haploid human genome is estimated to comprise 3 million to 4 billion base pairs. This extreme size precludes the analysis of DNA in its native form in routine molecular biology techniques. The techniques for identification and analysis of DNA became feasible and readily accessible with the discovery of enzymes termed restriction endonucleases.
These enzymes, originally isolated from bacteria, cut DNA into smaller sizes on the basis of specific recognition sites that vary from two to eight base pairs in length.5,6 The term restriction refers to the function of these enzymes in bacteria. A restriction endonuclease destroys foreign DNA (such as bacteriophage DNA) by cleaving the DNA at specific sites, thereby “restricting” the entry of foreign DNA in the bacterium. Several hundred restriction enzymes with different recognition sites are now commercially available. Because the recognition site for a given enzyme is fixed, the number and sizes of fragments generated for a particular DNA molecule remain consistent with the number of recognition sites and provide predictable patterns after separation by electrophoresis.
Analysis of the DNA fragments generated after digestion usually employs the technique of electrophoresis.7 Electrophoresis exploits the property that the phosphate groups in the DNA molecule confer a negative charge to that molecule. Thus, when a mixture of DNA molecules of different sizes is electrophoresed through a sieve (routinely either agarose or acrylamide), the longer DNA molecules migrate more slowly relative to the shorter fragments. Following electrophoresis, the separated DNA molecules can be located by a variety of staining techniques, of which ethidium bromide staining is a commonly used method.
Although staining with ethidium bromide is a versatile technique, analysis of a few hundred base pairs of DNA in the region of interest is difficult when the DNA from all the human chromosomes are cut and separated on the same gel. These limitations are circumvented by the technique of Southern blotting (named after its originator, Edward Southern) and the use of labeled radioactive or more commonly nonradioactive probes. Southern blotting involves digestion of DNA and separation by electrophoresis through agarose.8 After electrophoresis, the DNA is transferred to a solid support (such as nitrocellulose or nylon membranes), enabling the pattern of separated DNA fragments to be replicated onto the membrane (Figure 2-1). The DNA is then denatured (i.e., the two strands are physically separated), fixed to the membrane, and the dried membrane is mixed with a solution containing the DNA probe.
A DNA probe is a fragment of DNA that contains a nucleotide sequence specific for the gene or chromosomal region of interest. For purposes of detection, the DNA probe is labeled with an identifiable tag, such as radioactive phosphorus (e.g.,32P) or a chemiluminescent moiety; the latter has almost exclusively replaced radioactivity. The process of mixing the DNA probe with the denatured DNA fixed to the membrane is called hybridization, the principle being that there are only four nucleic acid bases in DNA—adenine (A), thymidine (T), guanine (G), and cytosine (C)—that always remain complementary on the two strands of DNA, A pairing with T, and G pairing with C. Following hybridization, the membrane is washed to remove the unbound probe and exposed to an x-ray film either in a process called autoradiography to detect radioactive phosphorus or in a process used to detect the chemiluminescent tag. Only those fragments that are complementary and have bound to the probe containing the DNA of interest will be evident on the x-ray film, enabling the analysis of the size and pattern of these fragments.
As routinely performed, the technique of Southern analysis can detect a single copy gene in as little as 5 µg of DNA, the DNA content of about 106 cells.FIGURE 2-1 ■. Southern blot. Fragments of double-stranded DNA are separated by size by agarose gel electrophoresis. To render the DNA single stranded (denatured), the agarose gel is soaked in an acidic solution. After neutralization of the acid, the gel is placed onto filter paper, the ends of which rest in a reservoir of concentrated salt buffer solution. A sheet of nitrocellulose membrane is placed on top of the gel and absorbent paper is stacked on top of the nitrocellulose membrane. The salt solution is drawn up through the gel by the capillary action of the filter paper wick and the absorbent paper towels. As the salt solution moves through the gel, it carries along with it the DNA fragments.
Because nitrocellulose binds single-stranded DNA, the DNA fragments are deposited onto the nitrocellulose in the same pattern that they were placed in the agarose gel. The DNA fragments bound to the nitrocellulose are fixed to the membrane by heat or UV irradiation. The nitrocellulose membrane with the bound DNA can then be used for procedures such as hybridization to a labeled DNA probe. Techniques to transfer DNA to other bonding matrices, such as nylon, are similar.(Adapted from Turco E, Fritsch R, Trucco M [1990]. Use of immunologic techniques in gene analysis. In Herberman RB, Mercer DW [eds.], Immunodiagnosis of cancer. New York: Marcel Dekker, 205.)Genomics, Epigenetics and GrowthGeert R. Mortier, Wim Vanden Berghe, in Human Growth and Development (Second Edition), 20127.5.1 Imprinting Defects and Human Growth DisordersThe human chromosome 11p15 encompasses two imprinted domains important in the control of fetal and postnatal growth (Figure 7.6). Each domain is differentially methylated and regulated by its own ICR. ICR1 is paternally methylated and located in the telomeric region of the 11p15 locus.
It regulates the H19 and IGF2 genes. ICR2 is maternally regulated and located in the centromeric region. It regulates the KCNQ1 and CDKN1C genes. Imprinting defects in these two domains are implicated in two clinically opposite growth disorders, the Silver–Russell syndrome (SRS) and the Beckwith–Wiedemann syndrome (BWS).26,29–31Figure 7.6. Schematic overview of imprinting at the Igf2/H19 loci on the human chromosome 11p15. This figure is reproduced in the color plate section.SRS is a genetic disorder characterized by prenatal and postnatal growth retardation. Mean birth weight at term is around 1900 g. Affected children have a proportionate short stature with normal head circumference. The average adult height of males is 151 cm and that of females is 139 cm.
Despite the normal head size, developmental delay and learning disabilities are not uncommon in children with SRS. Hypoglycemia is a well-known complication in the neonatal period. Food aversion and recurrent vomiting result in severe failure to thrive during infancy and early childhood.SRS is a genetically heterogeneous disorder. Different genetic defects have been identified in children with SRS.29,30 In over 50% of the children with SRS a loss of DNA methylation is found at ICR1 of the 11p15 locus. Hypomethylation at ICR1 causes epigenetic dysregulation of the H19 and IGF-2 genes, ultimately resulting in reduced expression of IGF2 with growth restriction as a consequence. H19 and IGF2 are both imprinted genes, with H19 only expressed on the maternal allele (paternal imprinting) and IGF2 only expressed on the paternal allele (maternal imprinting). H19 is a growth-suppressing gene, whereas IGF2 is a growth-stimulating gene.
The degree of hypomethylation at ICR1 seems to correlate with the severity of the growth phenotype as well as additional SRS diagnostic features. Other genetic defects identified in children with SRS include uniparental disomy (UPD) for chromosome 7 (see below) and structural chromosomal aberrations affecting genes that code for growth factors or GH (e.g. rearrangements at chromosome locus 17q25).BWS is a genetic disorder characterized by prenatal and postnatal overgrowth.31 Accelerated growth may start prenatally, usually in the last trimester, with increased birth weight and length as a result, or only manifest later on, after birth. At birth, polyhydramnios and large placenta are frequently seen. Growth velocity and bone age are advanced in the first 4–6 years of life, after which they may return to normal.
Adult height tends to be at the upper end of the normal range. Characteristic clinical findings in infants and children with BWS include macroglossia, umbilical hernia and hemihypertrophy. Intelligence is usually normal but learning difficulties have been reported particularly if neonatal hypoglycemia was present and untreated. Children with BWS have an increased risk for developing embryonal tumors, particularly before the age of 7 years. Wilms’ tumor (tumor of the kidneys) is most commonly observed. The risk of tumors is greater in children with hemihypertrophy, where one side of the body is more developed than the other side. The genetic basis of BWS is also complex.31 In 10% of children with BWS a gain of DNA methylation is found at the ICR1 locus. Loss of methylation at ICR2 is found in 60% of BWS cases.
There is also evidence that in both SRS and BWS patients multiple loci in the genome can show imprinting defects.32Although not yet completely understood, SRS and BWS can be used as models to decipher the functional link between the observed (epi)genetic mutations and the clinical features in individuals with disturbed growth. Thus, fetal and postnatal growth is epigenetically controlled by different ICRs at 11p15 and other chromosomal regions. Although DNA methylation defects in imprinting control regions in SRS and BWS are clearly established, little information is available regarding the mechanism responsible for defective ICR DNA methylation.
Despite mutation screening of several factors involved in the establishment and maintenance of methylation marks, including ZFP57, MBD3, DNMT1 and DNMT3L, the molecular clue for the ICR1/ICR2 hypomethylation remains unclear. Genetic analysis of H19 and the IGF2/H19 imprinting control region has uncovered various new genetic defects, including mutations and duplications that may be relevant in (epi)genetic (re)organization of the locus and etiology of SRS.33The use of assisted reproductive technology (ART) has been shown to induce epigenetic alterations and to affect fetal growth and development.
In humans, several imprinting disorders, including BWS, occur at significantly higher frequencies in children conceived with the use of ART than in children conceived spontaneously.34,35The cause of these epigenetic imprinting disorders associated with ART, including hormonal hyperstimulation, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), micromanipulation of gametes, exposure to culture medium, in vitro ovocyte maturation and time of transfer, remains unclear. However, recent data have shown that in patients with BWS or SRS, including those born following the use of ART, the DNA methylation defect involves imprinted loci other than 11p15 [11p15 region: CTCF binding sites at ICR1, H19 and IGF2 DMRs, KCNQ1OT1 (ICR2); SNRPN (chromosome 15 q11–13), PEG/MEST1 (chromosome 7q31), IGF-2 receptor and ZAC1 (chromosomes 6q26 and 6q24, respectively), DLK1/GTL2-IG-DMR (chromosome 14q32) and GNAS
locus (chromosome. #fastitlinks
To provide an example, the term “14q32” refers to the second band in the third region of the q arm of chromosome 14 (209). (It is not the case that the number 32 is read as thirty-two. Instead, it is read as three-two.) Another example is as follows. The breast cancer gene BRCA1 is located at 17q21.31. This means that the gene is located on the q arm of chromosome 17, in region 2. Within region 2, the gene is located in band 1. Collectively, this may be called, “band two, one.” Within band 21, the gene resides in sub-band 31. Regarding the number 31, the 3 refers to a sub-band, and the number 1 refers to a sub-band within sub-band 3 (210).
Molecular endocrinology and endocrine geneticsRam K. Menon MD, ... Constantine A. Stratakis MD, D(med)Sci, in Pediatric Endocrinology (Fourth Edition), 2014Isolation and digestion of DNA and southern blottingThe human chromosome comprises a long double-stranded helical molecule of DNA associated with different nuclear proteins.3,4 As DNA forms the starting point of the synthesis of all the protein molecules in the body, molecular techniques using DNA have proven to be crucial in the development of diagnostic tools to analyze endocrine diseases. DNA can be isolated from any human tissue, including circulating white blood cells. About 200 µg of DNA can be obtained from 10 to 20 mL of whole blood with the efficiency of DNA extraction being dependent on the technique used and the method of anticoagulation employed. The extracted DNA can be stored almost indefinitely at an appropriate temperature.
Furthermore, lymphocytes can be transformed with the Epstein-Barr virus (and other means) to propagate indefinitely in cell culture as “immortal” cell lines, thus providing a renewable source of DNA. For performing molecular genetic studies, lymphoid lines are routinely the tissue of choice, because a renewable source of DNA obviates the need to obtain further blood from the family. Fibroblast-derived cultures can also serve as a permanent source of DNA or RNA (once transformed), but they have to be derived from surgical specimens or a biopsy. It should be noted that, because the expression of many genes is tissue specific, immortalized lymphoid or fibroblastoid cell lines cannot be used to anlyze the abundance or composition of messenger RNA (mRNA) for a specific gene. Hence, studies involving mRNA necessitate the analysis of the tissue(s) expressing the gene as outlined in the section on “RNA Analysis” that begins on page 13.
DNA is present in extremely large molecules; the smallest chromosome (chromosome 22) has about 50 million base pairs and the entire haploid human genome is estimated to comprise 3 million to 4 billion base pairs. This extreme size precludes the analysis of DNA in its native form in routine molecular biology techniques. The techniques for identification and analysis of DNA became feasible and readily accessible with the discovery of enzymes termed restriction endonucleases.
These enzymes, originally isolated from bacteria, cut DNA into smaller sizes on the basis of specific recognition sites that vary from two to eight base pairs in length.5,6 The term restriction refers to the function of these enzymes in bacteria. A restriction endonuclease destroys foreign DNA (such as bacteriophage DNA) by cleaving the DNA at specific sites, thereby “restricting” the entry of foreign DNA in the bacterium. Several hundred restriction enzymes with different recognition sites are now commercially available. Because the recognition site for a given enzyme is fixed, the number and sizes of fragments generated for a particular DNA molecule remain consistent with the number of recognition sites and provide predictable patterns after separation by electrophoresis.
Analysis of the DNA fragments generated after digestion usually employs the technique of electrophoresis.7 Electrophoresis exploits the property that the phosphate groups in the DNA molecule confer a negative charge to that molecule. Thus, when a mixture of DNA molecules of different sizes is electrophoresed through a sieve (routinely either agarose or acrylamide), the longer DNA molecules migrate more slowly relative to the shorter fragments. Following electrophoresis, the separated DNA molecules can be located by a variety of staining techniques, of which ethidium bromide staining is a commonly used method.
Although staining with ethidium bromide is a versatile technique, analysis of a few hundred base pairs of DNA in the region of interest is difficult when the DNA from all the human chromosomes are cut and separated on the same gel. These limitations are circumvented by the technique of Southern blotting (named after its originator, Edward Southern) and the use of labeled radioactive or more commonly nonradioactive probes. Southern blotting involves digestion of DNA and separation by electrophoresis through agarose.8 After electrophoresis, the DNA is transferred to a solid support (such as nitrocellulose or nylon membranes), enabling the pattern of separated DNA fragments to be replicated onto the membrane (Figure 2-1). The DNA is then denatured (i.e., the two strands are physically separated), fixed to the membrane, and the dried membrane is mixed with a solution containing the DNA probe.
A DNA probe is a fragment of DNA that contains a nucleotide sequence specific for the gene or chromosomal region of interest. For purposes of detection, the DNA probe is labeled with an identifiable tag, such as radioactive phosphorus (e.g.,32P) or a chemiluminescent moiety; the latter has almost exclusively replaced radioactivity. The process of mixing the DNA probe with the denatured DNA fixed to the membrane is called hybridization, the principle being that there are only four nucleic acid bases in DNA—adenine (A), thymidine (T), guanine (G), and cytosine (C)—that always remain complementary on the two strands of DNA, A pairing with T, and G pairing with C. Following hybridization, the membrane is washed to remove the unbound probe and exposed to an x-ray film either in a process called autoradiography to detect radioactive phosphorus or in a process used to detect the chemiluminescent tag. Only those fragments that are complementary and have bound to the probe containing the DNA of interest will be evident on the x-ray film, enabling the analysis of the size and pattern of these fragments.
As routinely performed, the technique of Southern analysis can detect a single copy gene in as little as 5 µg of DNA, the DNA content of about 106 cells.FIGURE 2-1 ■. Southern blot. Fragments of double-stranded DNA are separated by size by agarose gel electrophoresis. To render the DNA single stranded (denatured), the agarose gel is soaked in an acidic solution. After neutralization of the acid, the gel is placed onto filter paper, the ends of which rest in a reservoir of concentrated salt buffer solution. A sheet of nitrocellulose membrane is placed on top of the gel and absorbent paper is stacked on top of the nitrocellulose membrane. The salt solution is drawn up through the gel by the capillary action of the filter paper wick and the absorbent paper towels. As the salt solution moves through the gel, it carries along with it the DNA fragments.
Because nitrocellulose binds single-stranded DNA, the DNA fragments are deposited onto the nitrocellulose in the same pattern that they were placed in the agarose gel. The DNA fragments bound to the nitrocellulose are fixed to the membrane by heat or UV irradiation. The nitrocellulose membrane with the bound DNA can then be used for procedures such as hybridization to a labeled DNA probe. Techniques to transfer DNA to other bonding matrices, such as nylon, are similar.(Adapted from Turco E, Fritsch R, Trucco M [1990]. Use of immunologic techniques in gene analysis. In Herberman RB, Mercer DW [eds.], Immunodiagnosis of cancer. New York: Marcel Dekker, 205.)Genomics, Epigenetics and GrowthGeert R. Mortier, Wim Vanden Berghe, in Human Growth and Development (Second Edition), 20127.5.1 Imprinting Defects and Human Growth DisordersThe human chromosome 11p15 encompasses two imprinted domains important in the control of fetal and postnatal growth (Figure 7.6). Each domain is differentially methylated and regulated by its own ICR. ICR1 is paternally methylated and located in the telomeric region of the 11p15 locus.
It regulates the H19 and IGF2 genes. ICR2 is maternally regulated and located in the centromeric region. It regulates the KCNQ1 and CDKN1C genes. Imprinting defects in these two domains are implicated in two clinically opposite growth disorders, the Silver–Russell syndrome (SRS) and the Beckwith–Wiedemann syndrome (BWS).26,29–31Figure 7.6. Schematic overview of imprinting at the Igf2/H19 loci on the human chromosome 11p15. This figure is reproduced in the color plate section.SRS is a genetic disorder characterized by prenatal and postnatal growth retardation. Mean birth weight at term is around 1900 g. Affected children have a proportionate short stature with normal head circumference. The average adult height of males is 151 cm and that of females is 139 cm.
Despite the normal head size, developmental delay and learning disabilities are not uncommon in children with SRS. Hypoglycemia is a well-known complication in the neonatal period. Food aversion and recurrent vomiting result in severe failure to thrive during infancy and early childhood.SRS is a genetically heterogeneous disorder. Different genetic defects have been identified in children with SRS.29,30 In over 50% of the children with SRS a loss of DNA methylation is found at ICR1 of the 11p15 locus. Hypomethylation at ICR1 causes epigenetic dysregulation of the H19 and IGF-2 genes, ultimately resulting in reduced expression of IGF2 with growth restriction as a consequence. H19 and IGF2 are both imprinted genes, with H19 only expressed on the maternal allele (paternal imprinting) and IGF2 only expressed on the paternal allele (maternal imprinting). H19 is a growth-suppressing gene, whereas IGF2 is a growth-stimulating gene.
The degree of hypomethylation at ICR1 seems to correlate with the severity of the growth phenotype as well as additional SRS diagnostic features. Other genetic defects identified in children with SRS include uniparental disomy (UPD) for chromosome 7 (see below) and structural chromosomal aberrations affecting genes that code for growth factors or GH (e.g. rearrangements at chromosome locus 17q25).BWS is a genetic disorder characterized by prenatal and postnatal overgrowth.31 Accelerated growth may start prenatally, usually in the last trimester, with increased birth weight and length as a result, or only manifest later on, after birth. At birth, polyhydramnios and large placenta are frequently seen. Growth velocity and bone age are advanced in the first 4–6 years of life, after which they may return to normal.
Adult height tends to be at the upper end of the normal range. Characteristic clinical findings in infants and children with BWS include macroglossia, umbilical hernia and hemihypertrophy. Intelligence is usually normal but learning difficulties have been reported particularly if neonatal hypoglycemia was present and untreated. Children with BWS have an increased risk for developing embryonal tumors, particularly before the age of 7 years. Wilms’ tumor (tumor of the kidneys) is most commonly observed. The risk of tumors is greater in children with hemihypertrophy, where one side of the body is more developed than the other side. The genetic basis of BWS is also complex.31 In 10% of children with BWS a gain of DNA methylation is found at the ICR1 locus. Loss of methylation at ICR2 is found in 60% of BWS cases.
There is also evidence that in both SRS and BWS patients multiple loci in the genome can show imprinting defects.32Although not yet completely understood, SRS and BWS can be used as models to decipher the functional link between the observed (epi)genetic mutations and the clinical features in individuals with disturbed growth. Thus, fetal and postnatal growth is epigenetically controlled by different ICRs at 11p15 and other chromosomal regions. Although DNA methylation defects in imprinting control regions in SRS and BWS are clearly established, little information is available regarding the mechanism responsible for defective ICR DNA methylation.
Despite mutation screening of several factors involved in the establishment and maintenance of methylation marks, including ZFP57, MBD3, DNMT1 and DNMT3L, the molecular clue for the ICR1/ICR2 hypomethylation remains unclear. Genetic analysis of H19 and the IGF2/H19 imprinting control region has uncovered various new genetic defects, including mutations and duplications that may be relevant in (epi)genetic (re)organization of the locus and etiology of SRS.33The use of assisted reproductive technology (ART) has been shown to induce epigenetic alterations and to affect fetal growth and development.
In humans, several imprinting disorders, including BWS, occur at significantly higher frequencies in children conceived with the use of ART than in children conceived spontaneously.34,35The cause of these epigenetic imprinting disorders associated with ART, including hormonal hyperstimulation, in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), micromanipulation of gametes, exposure to culture medium, in vitro ovocyte maturation and time of transfer, remains unclear. However, recent data have shown that in patients with BWS or SRS, including those born following the use of ART, the DNA methylation defect involves imprinted loci other than 11p15 [11p15 region: CTCF binding sites at ICR1, H19 and IGF2 DMRs, KCNQ1OT1 (ICR2); SNRPN (chromosome 15 q11–13), PEG/MEST1 (chromosome 7q31), IGF-2 receptor and ZAC1 (chromosomes 6q26 and 6q24, respectively), DLK1/GTL2-IG-DMR (chromosome 14q32) and GNAS
locus (chromosome. #fastitlinks
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