Abnormal Development - Genetic

From Embryology
Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

Introduction

Chromosomes in trisomy 21

This page gives a general introduction to information about genetic abnormalities their relationship to age, ethnicity and prenatal testing. Use the listed links for more information about specific abnormalities. In developed countries with increasing maternal age comes the increased risk of age related genetic abnormalities, such as trisomy 21.

In order to detect some genetic abnormalities many countries offer genetic screening programs that include maternal serum screening (MSS, for detection of Down's syndrome and neural tube defects), embryonic and newborn screening (for phenylketonuria (PKU), hypothyroidism, cystic fibrosis and metabolic disorders).

In terms of maternal/paternal family history, some ethnic backgrounds have been shown to have disease-associated genetic variants, though most common genetic diseases are consistent across ethnic boundaries. For example: Caucasians of northern European ancestry and cystic fibrosis (CTFR gene), Mediterranean, Asian and Far Eastern ancestry with beta-thalassaemia.

Note that the development of in vitro fertilization techniques now allows cells from early stage blastocysts to be removed and genetically analysed prior to implantation. This has raised some ethical issues relating to what parameters will be in future used in blastocyst selection.


Genetic Links: genetic abnormalities | maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | Trisomy X | trisomy mosaicism | Monosomy | Fragile X | Williams | Alagille | Philadelphia chromosome | mitochondria | VACTERL | hydatidiform mole | epigenetics | Prenatal Diagnosis | Neonatal Diagnosis | meiosis | mitosis | International Classification of Diseases | genetics

| Cell Division - Meiosis | Cell Division - Mitosis

Abnormality Links: abnormal development | abnormal genetic | abnormal environmental | Unknown | teratogens | ectopic pregnancy | cardiovascular abnormalities | coelom abnormalities | endocrine abnormalities | gastrointestinal abnormalities | genital abnormalities | head abnormalities | integumentary abnormalities | musculoskeletal abnormalities | limb abnormalities | neural abnormalities | neural crest abnormalities | placenta abnormalities | renal abnormalities | respiratory abnormalities | hearing abnormalities | vision abnormalities | twinning | Developmental Origins of Health and Disease |  ICD-11
Historic Embryology  
1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo | 1921 Rat and Man | 1966 Congenital Malformations

Some Recent Findings

Human idiogram
  • Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies[1] "Available evidence strongly supports the use of chromosomal microarray (CMA) in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages."
  • Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia[2] "Except for FLNB, HIC1 and ZNF189, maternal genes did not appear to influence the risk of clefting in our data. This is consistent with recent epidemiological findings showing no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefts in these two populations. It is likely that fetal genes make the major genetic contribution to clefting risk in these populations, but we cannot rule out the possibility that maternal genes can affect risk through interactions with specific teratogens or fetal genes."
  • Altered intra-nuclear organisation of heterochromatin and genes in ICF syndrome[3] "The ICF syndrome is a rare autosomal recessive disorder, the most common symptoms of which are immunodeficiency, facial anomalies and cytogenetic defects involving decondensation and instability of chromosome 1, 9 and 16 centromeric regions. ...DNA hypomethylation, previously reported to correlate with the decondensation of centromeric regions in metaphase described in these patients, appears also to correlate with the heterochromatin spatial configuration in interphase. "

Human Oocyte Aneuploidy

  • Frequency and distribution of chromosome abnormalities in human oocytes[4] "It was previously shown that more than half of the human oocytes obtained from IVF patients of advanced reproductive age are aneuploid, due to meiosis I and meiosis II errors. The present paper further confirms that 61.8% of the oocytes tested by fluorescent probes specific for chromosomes 13, 16, 18, 21 and 22 are abnormal, representing predominantly chromatid errors, which are the major source of aneuploidy in the resulting embryos. Almost half of the oocytes with meiosis I errors (49.3%) are prone to sequential meiosis II errors, which may lead to aneuploidy rescue in 30.8% of the cases. Half of the detected aneuploidies (49.8%) are of complex nature with involvement of two or more chromosomes, or the same chromosome in both meiotic divisions. The aneuploidy rates for individual chromosomes are different, with a higher prevalence of chromosome 21 and 22 errors. The origin of aneuploidy for the individual chromosomes is also not random, with chromosome 16 and 22 errors originating more frequently in meiosis II, and chromosome 18, 13 and 21 errors in meiosis I. There is an age dependence not only for the overall frequency of aneuploidies, but also for each chromosome error, aneuploidies originating from meiosis I, meiosis II, and both meiosis I and meiosis II errors, as well as for different types of aneuploidies. The data further suggest the practical relevance of oocyte aneuploidy testing for detection and avoidance from transfer of the embryos deriving from aneuploid oocytes, which should contribute significantly to the pregnancy outcomes of IVF patients of advanced reproduction age."


Links: Genetic risk maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | Oocyte Development

Human Chromosomes

Human idiogram
Human Chromosomes: 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y  
Idiogram Chromosome Banding - The term refers to the light and dark pattern, seen after staining with a dye, of individual chromosomes identified in metaphase. It is only in meiosis and mitosis during metaphase that chromosomes can be easily identified, during the normal cell life (interphase) the chromosomes are unravelled and distributed within the nucleus in chromosome territories. A band is that part of a chromosome which is clearly distinguishable from nearby regions by appearing darker or brighter with one or more banding techniques.
Human Idiogram: 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y
Genetic abnormality locations: 1-4 | 5-8 | 9-12 | 13-16 | 17-20 | 21-XY | sSMC
Inheritance Pattern images: Genetic Abnormalities | autosomal dominant | autosomal recessive | X-linked dominant (affected father) | X-Linked dominant (affected mother) | X-Linked recessive (affected father) | X-Linked recessive (carrier mother) | mitochondrial inheritance | Codominant inheritance | Genogram symbols | Genetics
Links: Genetics | Abnormal Development - Genetic

Cite this page: Hill, M.A. (2024, March 29) Embryology Abnormal Development - Genetic. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Genetic

What Links Here?
© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G


Genetic Inheritance

The figures below show the pattern of inheritance of a range of genetic disorders. In addition to these patterns are the known effects of increased maternal age and the effects of genetic mutations in the embryo and newborn.

Inheritance Pattern images: Genetic Abnormalities | autosomal dominant | autosomal recessive | X-linked dominant (affected father) | X-Linked dominant (affected mother) | X-Linked recessive (affected father) | X-Linked recessive (carrier mother) | mitochondrial inheritance | Codominant inheritance | Genogram symbols | Genetics

Genome-wide association study

The National Human Genome Research Institute (USA) lists publications as part of the genome-wide association study (GWAS) in an attempt to assay at least 100,000 single nucleotide polymorphisms (SNPs) in the initial stage.

Links: Genome-wide association study | National Human Genome Research Institute


Genetic Abnormality Topics

Trisomy

In humans, the most common trisomy is trisomy 21 or Down syndrome.

The term trisomy refers to the abnormal copy number of a specific chromosome, that is 3 copies instead of 2. The abnormality is identified by the chromosome that is present as 3 copies within the cell.


Mutagen

A chemical or agent that can cause permanent damage to the genetic material, DeoxyriboNucleic Acid (DNA) in a cell. DNA damage in the human oocyte or spermatozoa may lead to reduced fertility, spontaneous abortion (miscarriage), birth defects and heritable diseases. DNA damage postnatally can lead to a variety of tumours.

There are a large number of known mutagenic agents including those that are physical, chemical or biological in origin.

Bloodspot Test or Guthrie Test

Guthrie card

A blood screening test developed by Dr Robert Guthrie (1916-95) at University of Buffalo.[5] The test is carried out on neonatal (newborn) blood detecting markers for a variety of known disorders (phenylketonuria (PKU), hypothyroidism and cystic fibrosis).

Australia - NSW Newborn Screening Programme

Each year test more than 90,000 babies and detects about 90 who need urgent assessment and treatment. In NSW and Victoria, the bloodspot cards are currently stored indefinitely.

  • Phenylketonuria (PKU) - 1 in 10,000 live births (about 10 babies per year). PKU causes high blood levels of phenylalanine and severe intellectual disability. A diet low in phenylalanine, started in the first two to three weeks results in normal development.
  • Primary congenital hypothyroidism - 1 in 3,500 live births (about 26 babies per year). It is caused by the absence or abnormal formation or function of the thyroid gland. This causes growth and intellectual disability if not treated. Medication with thyroid hormone started early, results in normal growth and development.
  • Cystic Fibrosis (CF) - 1 in 2,500 live births (about 34 babies per year). Without treatment babies develop chest infections and often have very serious failure to thrive. Early institution of treatment greatly improves the health of babies with CF. Newborn bloodspot screening detects about 95% of babies with CF but also detects a few babies who may only be healthy carriers. For these babies a sweat test at about six weeks of age determines whether the baby has CF or is a healthy carrier.
  • Galactosaemia - 1 in 40,000 births (about 1-3 cases per year). Babies cannot process galactose, a component of lactose. Life-threatening liver failure and infections can occur. A galactose-free diet instituted in the first week is life saving.
  • Rarer metabolic disorders - Some fatty acid, organic acid and other amino acid defects can now be detected using Tandem Mass Spectrometry. These much rarer metabolic disorders affect about 15 – 18 babies per year. Early detection is important as diet and medications can treat most of these disorders. Without appropriate management they can cause severe disability or death.

Genetics services in NSW - coordinated by the NSW Genetics Service Advisory Committee, which is supported by the Statewide Services Development Branch of the Strategic Development Division, NSW Department of Health. (Information from NSW Health - Newborn Bloodspot Screening Policy 13-Nov-2006)


Links: Guthrie test | NSW Genetics Health

References

  1. <pubmed>20466091</pubmed>| DOI
  2. <pubmed>20634891</pubmed>
  3. <pubmed>20613881</pubmed>
  4. <pubmed>16192694</pubmed>
  5. <pubmed>14063511</pubmed>

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Terms

  • anaphase - (Greek, ana = up, again) Cell division term referring to the fourth mitotic stage, where the paired chromatids now separate and migrate to spindle poles. This is followed by telophase.
Mitosis Phases: prophase - prometaphase - metaphase - anaphase - telophase
  • anaphase B - Cell division term referring to the part of anaphase during which the poles of the mitotic spindle move apart. (More? Cell Division - Mitosis)
  • aneuploidy - Genetic term used to describe an abnormal number of chromosomes mainly (90%) due to chromosome malsegregation mechanisms in maternal meiosis I.
  • disomy - Genetic term referring to the presence of two chromosomes of a homologous pair in a cell, as in diploid. See chromosomal number genetic disorders uniparental disomy and aneuploidy. Humans have pairs usually formed by one chromosome from each parent.
  • meiosis I (MI) The first part of meiosis resulting in separation of homologous chromosomes, in humans producing two haploid cells (N chromosomes, 23), a reductional division.
Meiosis I: Prophase I - Metaphase I - Anaphase I - Telophase I
  • meiosis II - (MII) The second part of meiosis. In male human spermatogenesis, producing of four haploid cells (23 chromosomes, 1N) from the two haploid cells (23 chromosomes, 1N), each of the chromosomes consisting of two sister chromatids produced in meiosis I. In female human oogenesis, only a single haploid cell (23 chromosomes, 1N) is produced.
Meiosis II: Prophase II - Metaphase II - Anaphase II - Telophase II
  • prometaphase - (Greek, pro = before) Cell division term referring to the second mitotic stage, when the nuclear envelope breaks down into vesicles. Microtubules then extend from the centrosomes at the spindle poles (ends) and reach the chromosomes. This is followed by metaphase.
  • Philadelphia chromosome - (Philadelphia translocation) Genetic term referring to a chromosomal abnormality resulting from a reciprocal translocation between chromosome 9 and 22 (t(9;22)(q34;q11)). This is associated with the disease chronic myelogenous leukemia (CML).
  • prophase - (Greek, pro = before) Cell division term referring to the first mitotic stage, when the diffusely stained chromatin resolves into discrete chromosomes, each consisting of two chromatids joined together at the centromere.
  • telophase - Cell division term referring to the fifth mitotic stage, where the vesicles of the nuclear envelope reform around the daughter cells, the nucleoli reappear and the chromosomes unfold to allow gene expression to begin. This phase overlaps with cytokinesis, the division of the cell cytoplasm.
  • uniparental disomy - Genetic term referring to cells containing both copies of a homologous pair of chromosomes from one parent and none from the other parent.

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Cite this page: Hill, M.A. (2024, March 29) Embryology Abnormal Development - Genetic. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Genetic

What Links Here?
© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G