Chromosomal Aberrations in Humans

Overview of Chromosomal Aberrations in Humans

Chromosomal aberrations are changes in the number or structure of chromosomes. In humans, they are a major cause of infertility, miscarriages, congenital malformations, and developmental disorders. This chapter focuses on the types of chromosomal aberrations seen in humans, their typical consequences, and the basic principles behind how they arise and are detected.

(Details of chromosome structure, meiosis, and Mendelian inheritance are treated elsewhere; here we assume those basics.)

Broadly, chromosomal aberrations are divided into:

• Numerical aberrations – changes in chromosome number (e.g. trisomies, monosomies).
• Structural aberrations – changes in chromosome structure (e.g. deletions, duplications, translocations, inversions, ring chromosomes, isochromosomes).

They can affect autosomes (non–sex chromosomes) or sex chromosomes; sex-chromosome aberrations are treated in a separate subchapter.

How Chromosomal Aberrations Arise

Nondisjunction and Anaphase Lag

Most numerical aberrations arise by errors during meiosis:

• Nondisjunction: homologous chromosomes (in meiosis I) or sister chromatids (in meiosis II) fail to separate. As a result:
• One gamete receives two copies of a chromosome (n+1),
• The other gamete no copy (n−1).

After fertilization with a normal gamete (n):

• $(n+1) + n \to 2n+1$ → trisomy (three copies of a chromosome).
• $(n-1) + n \to 2n-1$ → monosomy (one copy of a chromosome).

Occasionally, errors occur in mitosis after fertilization, leading to mosaicism: the body contains two or more genetically different cell lines (e.g. some cells trisomic, others normal).

Anaphase lag is another mechanism: a chromosome or chromatid fails to be incorporated into the daughter nucleus and is lost, potentially creating monosomic or mosaic cell lines.

Structural Rearrangements and DNA Breakage

Structural aberrations usually arise from double-strand DNA breaks and incorrect rejoining:

• Breaks in one or multiple chromosomes.
• Rejoining in abnormal arrangements.
• Loss or gain of chromosomal segments.

These changes may be:

• Balanced – no net gain or loss of genetic material (e.g. many translocations, inversions).
• Unbalanced – net gain or loss of material (e.g. deletions, duplications, some translocations).

Balanced aberrations often have no outward effect in the carrier but can produce unbalanced gametes and affected offspring.

Germline vs. Somatic Aberrations

• Germline aberrations: present in egg or sperm; after fertilization, they are found in all cells of the offspring (unless mosaicism occurs). These are responsible for congenital syndromes and heritable chromosomal disorders.
• Somatic aberrations: arise during mitosis in body cells and are not passed to offspring. They are especially important in cancer, where specific chromosomal rearrangements can activate oncogenes or inactivate tumor suppressor genes.

Types of Numerical Chromosomal Aberrations

Aneuploidy

Aneuploidy = gain or loss of single chromosomes relative to the normal set (46 in humans).

Main forms:

• Trisomy: $2n + 1$ (47 chromosomes)
• Monosomy: $2n - 1$ (45 chromosomes)
• Tetrasomy: $2n + 2$ (48 chromosomes, four copies of one chromosome)
• Nullisomy ($2n - 2$) is lethal in humans and not seen in live births.

Most autosomal monosomies and many trisomies lead to very early embryonic death and miscarriage. Only a few specific trisomies are compatible with survival to birth and beyond.

Common Autosomal Trisomies in Liveborns

Although individual syndromes are discussed in detail elsewhere, it is useful to overview the three most frequent autosomal trisomies:

• Trisomy 21 (Down syndrome):
• Most common viable autosomal trisomy.
• Typically caused by meiotic nondisjunction; risk rises with increasing maternal age.
• Mosaic forms and translocation forms also occur.
• Trisomy 18 (Edwards syndrome) and Trisomy 13 (Patau syndrome):
• Far less common than trisomy 21.
• Often associated with severe malformations and high infant mortality.

Other full autosomal trisomies are usually embryonically lethal.

Polyploidy

Polyploidy = an entire extra set (or sets) of chromosomes.

• Triploidy: $3n = 69$ chromosomes.
• Tetraploidy: $4n = 92$ chromosomes.

Mechanisms include:

• Fertilization of one egg by two sperm (dispermy).
• Failure of meiotic division in a gamete (diploid gamete) followed by normal fertilization.
• Complete failure of mitotic division (for tetraploidy).

In humans, polyploidy is usually lethal before or shortly after birth. It is common in early miscarriages but rare among liveborns.

Structural Chromosomal Aberrations in Humans

Deletions

A deletion is loss of a chromosome segment.

Types:

• Terminal deletion: break near the end; the distal fragment is lost.
• Interstitial deletion: two breaks within a chromosome; the middle piece is lost and ends rejoin.

Consequences:

• Loss of multiple genes, often with haploinsufficiency (one copy is not enough for normal function).
• Larger deletions → more severe or lethal phenotypes.
• Some recognizable microdeletion syndromes involve very small deletions detectable only by high-resolution methods (e.g. FISH, microarrays).

Phenotypic effects typically include:

• Characteristic pattern of malformations and dysmorphic features.
• Developmental delay and/or intellectual disability.
• Possible organ-specific defects depending on genes lost.

Duplications

A duplication is a repeated chromosome segment.

• Tandem duplication: inserted next to the original.
• Displaced duplication: inserted elsewhere on the same chromosome or another chromosome.

They cause partial trisomy (three copies of genes in the duplicated region). Clinical severity depends on:

• Size of duplicated region.
• Gene content and dosage sensitivity.

Duplications can arise de novo or as unbalanced products from a parent's balanced rearrangement (e.g. translocation).

Inversions

An inversion occurs when a segment of a chromosome is reversed end to end after breakage and rejoining.

Two main types:

• Paracentric inversion: does not include the centromere.
• Pericentric inversion: includes the centromere.

In many carriers:

• The inversion is balanced (no loss or gain of material).
• They are often phenotypically normal.

However, problems arise in meiosis:

• Pairing of inverted and normal homolog leads to inversion loops.
• Crossing-over inside the loop can produce unbalanced gametes with duplications and deletions.
• Consequences: recurrent miscarriages or malformed offspring, even if the carrier is healthy.

Translocations

A translocation is an exchange of segments between non-homologous chromosomes.

Reciprocal Translocations

Two non-homologous chromosomes exchange segments.

• Typically balanced in carriers, who often show no clinical symptoms.
• During meiosis, chromosomes form complex configurations.
• Segregation can produce unbalanced gametes leading to:
• Miscarriages.
• Children with partial monosomies/partial trisomies.

This pattern (healthy parent with balanced translocation + multiple miscarriages or a child with an unbalanced karyotype) is a classic scenario in human genetics.

Robertsonian Translocations

Special type involving acrocentric chromosomes (13, 14, 15, 21, 22), whose centromere is near one end.

Mechanism:

• Fusion of the long arms of two acrocentric chromosomes at or near their centromeres.
• Short arms are usually lost (contain mostly rRNA genes, which are present in multiple copies elsewhere).

Carriers:

• Have 45 chromosomes, but total essential genetic material is roughly normal → often phenotypically normal.
• However, during meiosis they can produce:
• Balanced gametes (including or excluding the fused chromosome appropriately).
• Unbalanced gametes with extra or missing long arms (e.g. leading to trisomy 21 when involving chromosome 21).

A classic example is a Robertsonian translocation involving chromosome 21, which can cause familial Down syndrome.

Ring Chromosomes

A ring chromosome forms when both ends of a chromosome break and the remaining ends fuse, creating a ring.

Consequences:

• Terminal segments (and genes) at both ends are usually lost.
• Ring chromosomes can be unstable during mitosis, leading to mosaicism.
• Clinical features depend on which chromosome is affected and how much material is lost.

Isochromosomes

An isochromosome has two identical arms (either two short arms or two long arms) instead of one short and one long.

Mechanism:

• Misdivision of the centromere in the wrong plane.
• Loss of one arm, duplication of the other.

Results:

• Partial monosomy for genes on the missing arm.
• Partial trisomy for genes on the duplicated arm.

In humans, an important example is the isochromosome of the long arm of the X chromosome (i(Xq)), which is relevant for certain sex-chromosome syndromes.

Mosaicism and Chimerism

Mosaicism

Mosaicism means the presence of two or more genetically distinct cell populations derived from a single fertilized egg.

It often arises from:

• Postzygotic nondisjunction or anaphase lag (e.g. some cells 46, some 47).
• Structural rearrangements occurring in a subset of cells.

Consequences:

• Phenotype can be milder than in the corresponding non-mosaic condition, because some cells are normal.
• Clinical expression can be highly variable, depending on:
• Proportion of abnormal cells.
• Which tissues/organs contain them.
• Sometimes detectable only by analyzing multiple tissues or many cells.

Chimerism

Chimerism = genetically distinct cell populations derived from two different zygotes.

Mechanisms include:

• Fusion of two embryos (e.g. “tetragametic chimera”).
• Maternal–fetal cell exchange.

Chimerism is less common but can complicate genetic testing and blood typing. It is conceptually distinct from mosaicism, though both produce mixed cell populations.

Clinical and Reproductive Consequences

Miscarriage and Infertility

A very large proportion of early miscarriages are due to chromosomal aberrations, particularly:

• Autosomal monosomies.
• Many trisomies.
• Polyploidies.
• Large unbalanced structural rearrangements.

Couples with recurrent miscarriages are often tested for a balanced structural rearrangement (e.g. Robertsonian or reciprocal translocation) in one of the parents.

Chromosomal anomalies can also underlie:

• Infertility (e.g. due to impaired gametogenesis).
• Certain forms of gonadal dysgenesis (details in sex chromosome chapter).

Congenital Syndromes and Developmental Disorders

Chromosomal aberrations present from conception can lead to:

• Characteristic constellations of:
• Growth abnormalities.
• Congenital malformations.
• Intellectual disability.
• Specific facial or skeletal features.
• Organ-specific defects (e.g. heart defects, kidney anomalies, immune deficiencies).

Many named syndromes result from specific deletions, duplications, or trisomies. These are often diagnosed cytogenetically or by molecular methods.

Detection and Diagnosis of Chromosomal Aberrations

Classical Karyotyping

Karyotyping uses microscopic analysis of chromosomes from dividing cells (often lymphocytes):

1. Cells are arrested in metaphase, when chromosomes are condensed.
2. Chromosomes are stained to yield banding patterns (e.g. G-bands).
3. A karyotype is arranged and analyzed for:
• Number of chromosomes (e.g. 46,XX; 47,XY,+21).
• Large structural changes (e.g. translocations, large deletions).

Karyotyping is well suited for:

• Large-scale numerical changes (trisomies, monosomies, polyploidies).
• Macro-structural changes (large translocations, inversions, duplications).

Limitations:

• Resolution is limited (changes smaller than a few megabases may not be visible).

Fluorescence In Situ Hybridization (FISH)

FISH uses fluorescently labeled DNA probes that bind to specific chromosome regions.

Applications:

• Detecting presence/absence of specific chromosomes or segments (e.g. confirming trisomy 21, microdeletions).
• Identifying translocation partners by dual-color probes.
• Interphase FISH allows rapid analysis without needing metaphase spreads.

Chromosomal Microarray (Array-CGH, SNP Arrays)

Microarray-based methods compare patient DNA to a reference or analyze copy number across the genome.

They can detect:

• Submicroscopic deletions and duplications (copy number variants).
• Many microdeletion/microduplication syndromes.

Advantages:

• Higher resolution than classical karyotyping.

Limitations:

• Cannot reliably detect balanced rearrangements (no gain/loss of material).
• Interpretation of variants of uncertain significance can be challenging.

Prenatal and Preimplantation Diagnosis

Chromosomal aberrations can be identified before birth:

• Prenatal diagnosis:
• Sampling fetal cells via chorionic villus sampling (CVS) or amniocentesis.
• Karyotyping, FISH, and/or microarray on fetal DNA.
• Non-invasive prenatal testing (NIPT):
• Analysis of cell-free fetal DNA in maternal blood.
• Used primarily for screening common trisomies (e.g. 21, 18, 13).
• Preimplantation genetic testing (PGT):
• Embryos created via in vitro fertilization are tested before transfer to the uterus.
• Can detect aneuploidy or specific unbalanced rearrangements.

These methods raise important ethical, legal, and counseling questions, discussed elsewhere.

Balanced vs. Unbalanced Aberrations and Genetic Counseling

A key distinction for human genetics is balanced vs. unbalanced:

• Balanced aberration:
• No net loss or gain of essential genetic material.
• Carrier often phenotypically normal.
• However, during meiosis, segregation may produce unbalanced gametes, increasing risk of:
• Miscarriage,
• Infertility,
• Children with congenital anomalies.
• Unbalanced aberration:
• Net gain/loss of genetic material (partial monosomy/trisomy).
• Typically associated with clinical symptoms.

Genetic counseling for families with chromosomal aberrations addresses:

• Recurrence risk:
• Higher if a parent carries a balanced translocation or inversion.
• Often low if the aberration is a de novo event in the child.
• Options for reproductive planning:
• Prenatal diagnosis.
• Preimplantation genetic testing.
• Use of donor gametes or adoption.
• Psychosocial support and information on prognosis and management.

Chromosomal Aberrations in Cancer

Many cancers harbor somatic chromosomal aberrations that are not present in the germline and are not transmitted to offspring.

Examples (without going into disease-specific detail):

• Translocations creating novel fusion genes that promote uncontrolled growth.
• Amplifications (multiple copies) of oncogenes.
• Deletions affecting tumor suppressor genes.

These cancer-specific chromosomal changes:

• Can be used as diagnostic markers.
• May guide targeted therapies.
• Illustrate how chromosomal rearrangements can fundamentally alter cell behavior even outside the context of inherited disease.

Summary

• Chromosomal aberrations in humans include numerical (aneuploidies, polyploidies) and structural (deletions, duplications, translocations, inversions, ring chromosomes, isochromosomes) changes.
• They arise from nondisjunction, errors in DNA repair, and abnormal segregation during meiosis or mitosis.
• While many aberrations are lethal early in development, some are compatible with life and cause characteristic congenital syndromes and developmental disorders.
• Balanced rearrangements may be clinically silent in carriers but confer significant reproductive risks.
• Detection relies on karyotyping, FISH, chromosomal microarrays, and specialized prenatal or preimplantation techniques.
• Understanding chromosomal aberrations is essential for clinical genetics, reproductive counseling, and interpretation of both inherited and cancer-related genomic changes.