Page 2 of 6

AN75.1-5 | Principles of Genetics, Chromosomal Aberrations & Clinical Genetics — Part 1

Numerical Chromosomal Aberrations

Numerical aberrations involve changes in the total number of chromosomes. They are classified as euploidy (changes involving complete sets of 23 chromosomes) and aneuploidy (changes involving individual chromosomes).

Figure: Numerical Chromosomal Aberrations

Euploidy abnormalities include triploidy (69 chromosomes, 3n) and tetraploidy (92 chromosomes, 4n). Triploidy occurs in approximately 1-3% of all conceptions but is almost invariably lethal; most triploid conceptuses abort spontaneously in the first trimester. The rare cases surviving to the second trimester show severe intrauterine growth restriction, a disproportionately large head, and syndactyly. Triploidy arises from three mechanisms: dispermy (fertilisation of a normal ovum by two sperm — the most common cause, ~66%), diploid sperm (failure of meiosis II in spermatogenesis), or diploid ovum (failure of meiosis II in oogenesis). The phenotype depends on the parental origin of the extra set: diandric triploidy (extra paternal set) produces a partial hydatidiform mole with an abnormally large placenta, while digynic triploidy (extra maternal set) produces severe asymmetric growth restriction with a small placenta. Tetraploidy (4n) arises from failure of an early mitotic division and is uniformly lethal.

Aneuploidy — the gain or loss of individual chromosomes — is the most clinically significant category. Trisomy (2n+1 = 47 chromosomes) and monosomy (2n-1 = 45 chromosomes) are the two main types. The primary mechanism is non-disjunction: the failure of homologous chromosomes (in meiosis I) or sister chromatids (in meiosis II) to separate properly during cell division. When non-disjunction occurs in meiosis, the resulting gametes have either two copies (n+1) or no copies (n-1) of the affected chromosome. Fertilisation of an n+1 gamete by a normal n gamete produces a trisomy; fertilisation of an n-1 gamete produces a monosomy.

The relationship between maternal age and non-disjunction is one of the most important concepts in clinical genetics. The risk of trisomy increases exponentially with maternal age, particularly after age 35. The biological basis relates to the prolonged arrest of oocytes in prophase I of meiosis I (dictyotene stage). Oogenesis begins during foetal life, and primary oocytes remain arrested for decades — from before birth until ovulation. Over time, the cohesion proteins holding homologous chromosomes together degrade, increasing the probability of non-disjunction. For Down syndrome (trisomy 21), the risk increases from approximately 1 in 1,500 at maternal age 20 to 1 in 350 at age 35, 1 in 100 at age 40, and 1 in 25 at age 45. However, because younger women have more pregnancies, the majority of Down syndrome children are actually born to mothers under 35.

Non-disjunction in meiosis I vs. meiosis II has different consequences. In meiosis I non-disjunction, the trisomic offspring inherits both homologues from one parent (including any heterozygous regions), while in meiosis II non-disjunction, the offspring inherits two copies of the same homologue (identical for all loci). Molecular cytogenetic techniques (using DNA polymorphisms) can distinguish these two mechanisms and determine the parent of origin — approximately 90% of trisomy 21 cases result from maternal non-disjunction, predominantly in meiosis I.

Anaphase lag is an alternative mechanism for producing aneuploidy: a chromosome fails to attach to the mitotic spindle during cell division and is lost. If this occurs in the early post-zygotic mitotic divisions, it produces mosaicism — the coexistence of two or more cell lines with different chromosome constitutions in the same individual, derived from a single zygote.

Structural Chromosomal Aberrations

Structural aberrations result from chromosome breakage followed by abnormal reunion. They may be balanced (no net gain or loss of genetic material, usually phenotypically normal but with reproductive risks) or unbalanced (gain or loss of genetic material, usually phenotypically abnormal). The major types are:

Figure: Structural Chromosomal Aberrations

Translocation — transfer of chromosomal material between non-homologous chromosomes. Two types: (1) Reciprocal translocation: mutual exchange of segments between two chromosomes. Carriers are usually phenotypically normal because they have the complete genetic complement, but during meiosis, the translocated chromosomes must form a quadrivalent (a complex of four chromosomes) for pairing. Segregation of this quadrivalent can produce gametes with unbalanced chromosome complements, leading to recurrent miscarriages, congenital anomalies, or intellectual disability in offspring. The risk of unbalanced offspring depends on the chromosomes involved and the size of the translocated segments. (2) Robertsonian translocation: fusion of the long arms of two acrocentric chromosomes (13, 14, 15, 21, 22) at their centromeres, with loss of the short arms. The carrier has 45 chromosomes but is phenotypically normal because the lost short arms contain only ribosomal RNA genes (which are present in multiple copies on other acrocentric chromosomes). The most common Robertsonian translocation is rob(13;14), occurring in approximately 1 in 1,300 individuals. The clinically most important is rob(14;21), because carriers can produce offspring with translocation Down syndrome — this is the mechanism by which young parents can have a child with Down syndrome. A female rob(14;21) carrier has approximately a 10-15% empirical risk of having a liveborn child with Down syndrome, while a male carrier has approximately a 1-2% risk.

Deletion — loss of a chromosomal segment. Terminal deletions involve loss from one end of a chromosome; interstitial deletions involve loss from within the chromosome. Clinically important deletion syndromes include: Cri du chat syndrome (5p deletion — characteristic high-pitched cat-like cry in infancy, microcephaly, severe intellectual disability, round face with hypertelorism); Wolf-Hirschhorn syndrome (4p deletion — 'Greek helmet' facies, microcephaly, growth restriction, seizures, cardiac defects); and DiGeorge/velocardiofacial syndrome (22q11.2 deletion — the most common microdeletion syndrome, with an incidence of 1 in 4,000; features include conotruncal cardiac defects, palatal abnormalities, hypocalcaemia from parathyroid hypoplasia, thymic hypoplasia with immunodeficiency, and characteristic facial features).

Duplication — presence of an extra copy of a chromosomal segment, resulting in partial trisomy. Generally less severe than deletions of equivalent size.

Inversion — a chromosomal segment breaks at two points, rotates 180 degrees, and reinserts. Paracentric inversions do not include the centromere; pericentric inversions include the centromere. Inversion carriers are usually phenotypically normal, but during meiosis, the inverted segment must form an inversion loop for homologous pairing. Crossing over within the loop can produce unbalanced recombinant chromosomes with duplications and deletions, leading to abnormal offspring or recurrent pregnancy loss.

Ring chromosome — deletion of both terminal segments of a chromosome followed by fusion of the remaining broken ends. Ring chromosomes are unstable during mitosis and may be lost (leading to monosomy in some cell lines) or undergo sister chromatid exchange (producing larger and smaller rings).

Isochromosome — a chromosome in which one arm is duplicated and the other is deleted, resulting in two copies of one arm. The most clinically significant is isochromosome Xq, i(Xq), which accounts for approximately 15% of Turner syndrome cases — these individuals have two copies of the long arm of X but are missing the short arm.

Mosaicism and Chimerism

Mosaicism (AN75.2) refers to the presence of two or more genetically distinct cell lines within a single individual, all derived from a single zygote. Mosaicism arises from errors in mitotic cell division after fertilisation — either non-disjunction or anaphase lag in early post-zygotic mitoses. The earlier the mitotic error occurs, the greater the proportion of abnormal cells and the more severe the phenotype.

Figure: Mosaicism and Chimerism

Chromosomal mosaicism is clinically important in several contexts. (1) Mosaic Down syndrome (47,XX/XY,+21 / 46,XX/XY): accounts for approximately 2-4% of Down syndrome cases. Individuals with mosaicism typically have milder phenotypic features and higher cognitive function than those with complete trisomy 21, though the severity depends on the proportion and distribution of trisomic cells. (2) Mosaic Turner syndrome (45,X/46,XX or 45,X/46,XY): the most common karyotype in liveborn Turner syndrome individuals. Those with 45,X/46,XX mosaicism may have milder features, including spontaneous puberty and even fertility in some cases. The 45,X/46,XY mosaic presents a complex clinical scenario — these individuals may present anywhere along the spectrum from phenotypic female (with Turner features) to ambiguous genitalia to phenotypic male (with possible gonadoblastoma risk in dysgenetic gonads). (3) Confined placental mosaicism (CPM): the abnormal cell line is present only in the placenta (trophoblast-derived tissues), while the foetus has a normal karyotype. CPM can be detected on chorionic villus sampling (CVS) and may cause false-positive prenatal diagnosis results if amniocentesis is not performed for confirmation. It can also lead to intrauterine growth restriction if the abnormal cell line compromises placental function.

Somatic mosaicism also underlies several conditions not detectable on standard karyotyping: McCune-Albright syndrome (postzygotic activating GNAS1 mutation — polyostotic fibrous dysplasia, café-au-lait spots, precocious puberty), Proteus syndrome (AKT1 somatic mutation — progressive, asymmetric overgrowth), and some presentations of neurofibromatosis type 1 (segmental NF1).

Chimerism is fundamentally different from mosaicism: a chimera is an individual composed of cells derived from two or more different zygotes. This can occur through: (1) Tetragametic chimerism (previously called 'true chimerism'): the fusion of two dizygotic twin embryos very early in development. The resulting individual has two genetically distinct cell lines, each from a different zygote. This can produce striking phenotypic effects — if the two embryos were of different sex, the individual may have both 46,XX and 46,XY cell lines, potentially resulting in ovotesticular disorder of sex development (previously 'true hermaphroditism'). If the embryos had different blood groups, the individual will have two distinct red blood cell populations. (2) Blood chimerism in dizygotic twins: shared placental circulation between dizygotic twins can result in exchange of haematopoietic stem cells, producing lifelong blood group chimerism without affecting other tissues. (3) Microchimerism: the exchange of small numbers of cells between mother and foetus during pregnancy. Foetal cells can persist in the maternal circulation for decades after pregnancy (foetal microchimerism), and maternal cells similarly persist in offspring. The clinical significance of microchimerism is still being investigated, with possible roles in autoimmune disease and transplant tolerance.

The distinction between mosaicism and chimerism is clinically important: mosaicism arises from a mitotic error in a single zygote (the two cell lines are genetically related, differing only at the site of the error), while chimerism arises from the fusion or mixing of cells from genetically distinct zygotes (the two cell lines may differ across the entire genome, including at polymorphic loci).