Structural Chromosome Rearrangements and Aberrations

Chromosome Nomenclature and Karyotyping

  • Autosome Assignment:

    • Autosomes are designated by numbers 1 through 22 based on chromosome size (with chromosome 22 as an exception to the size ordering rule).

  • Sex Chromosomes:

    • Sex chromosomes are denoted by the letters X and Y.

  • Karyotype Description Essentials:

    • A standardized karyotype description provides the total number of chromosomes, the sex chromosome complement, and a precise description of any structural or numerical chromosomal abnormalities.

    • Normal Male Karyotype: 46,XY.

    • Superfemale Karyotype: 47,XXX.

Banding and Staining Techniques

  • Historical Context and Purpose:

    • Chromosome banding was launched in the early 1970s.

    • It allows for the definitive identification of chromosomes not only by length and centromere position, but also by their unique, characteristic banding properties.

  • Chromosome Regions and Bands:

    • Chromosome regions are defined as areas lying between two distinct morphological landmarks and are further subdivided into specific bands.

  • Global vs. Structural-Specific Banding:

    • G-banding, Q-banding, and R-banding produce bands distributed along the entire length of the chromosome.

    • C-banding, T-banding, and NOR-staining identify specific, heritable structural features of chromosomes.

  • G-banding:

    • Chromosomes are pre-treated with trypsin to partially digest chromosomal proteins prior to staining with Giemsa stain.

    • Produces specific banding patterns for each pair of homologous chromosomes similar to Q-banding.

    • Adenine-Thymine (AT)-rich, gene-poor regions stain darkly.

  • Q-banding:

    • Utilizes the fluorescent stain quinacrine dihydrochloride.

    • AT-rich, gene-poor regions fluoresce brightly.

    • Highly effective for identifying centromeric regions of chromosomes 3, 4, and 13, certain acrocentric chromosomes, and the Y chromosome.

  • R-banding (Reverse Banding):

    • Chromosomes are heated in a phosphate buffer before staining.

    • Produces a banding pattern that is the exact reverse of G-banding.

  • C-banding:

    • Chromosomes undergo barium hydroxide treatment followed by Giemsa staining.

    • Selectively stains constitutive heterochromatin located close to centromeres and on the long arm of the Y chromosome.

    • Used to identify dicentric chromosomes and variations in constitutive heterochromatin.

  • T-banding:

    • A Giemsa staining technique that specifically stains the telomeres (ends) and centromeres of chromosomes.

  • NOR (Nucleolar Organizer Region) Staining:

    • Utilizes silver nitrate, which preferentially accumulates in the Nucleolar Organizer Regions located on the stalks of acrocentric chromosomes containing active ribosomal RNA (rRNA) genes.

Structural Chromosome Rearrangements

  • Mechanism of Formation:

    • Exchange of genetic material between sister chromatids and homologous chromosomes occurs normally during cell division.

    • Structural rearrangements result when exchanges occur between non-allelic chromosomal regions.

  • Primary Rearrangement Categories:

    • Balanced Rearrangements: No net loss or gain of genetic information occurs; individuals are generally phenotypically normal.

    • Unbalanced Rearrangements: Additional and/or missing genetic material is present; individuals are clinically affected.

    • Familial Rearrangements: Structural rearrangements passed down through multiple generations of a family.

    • De Novo Rearrangements: Newly arisen rearrangements where the exact molecular mechanism is unknown and no other affected family members exist for comparison.

Types of Aberrant Chromosomes

  • Dicentric Chromosomes:

    • Formed from any chromosomal exchange in which both the donor and recipient segments contain a centromere, resulting in a single chromosome with two centromeres.

  • Acentric Chromosomes:

    • Chromosomes or chromosomal fragments that lack a centromere.

    • Because the centromere is essential for spindle attachment and proper segregation during division, acentric fragments are rapidly lost.

    • Single cells with acentric fragments may be observed occasionally, but constitutional karyotypes containing a true acentric chromosome are never seen in live individuals.

  • Isochromosomes:

    • Consist of two identical copies of the same chromosome arm joined through a single centromere, forming mirror images of each other.

    • An individual with 46 chromosomes containing one isochromosome is monosomic for the genes on the missing arm and trisomic for all genes present on the duplicated isochromosome arm.

  • Ring Chromosomes:

    • Formed by breaks in both the short and long arms of a chromosome, followed by fusion of the broken ends and complete loss of the distal segments.

Chromosomal Deletions

  • Definition:

    • A genetic aberration wherein a portion of a chromosome or DNA sequence is left out during DNA replication.

    • Can range in size from a single nucleotide base pair to an entire chromosomal segment.

  • Structural Types of Deletions:

    • Terminal Deletions: Result from a single chromosomal break with the subsequent loss of the segment distal to the break.

    • Interstitial Deletions: Result from two breaks within a single chromosome, loss of the intervening genetic segment, and rejoining of the outer breakpoints.

Deletion Syndromes and Clinical Features

  • Monosomy 1p36:

    • Deleted Region: 1p36

    • Clinical Features: Mental retardation, growth delay, hypotonia, early puberty, deafness, eye problems, cardiomyopathy, seizures and/or abnormal EEGs, enlarged anterior fontanel, deep-set eyes, flat nasal bridge, orofacial clefting or palatal abnormalities, pointed chin, and ear abnormalities.

  • Wolf-Hirschhorn Syndrome:

    • Deleted Region: 4p

    • Clinical Features: Mental and growth retardation, microcephaly, hypertelorism, broad nasal bridge, downturned mouth, cleft lip and/or palate, micrognathia, cryptorchidism, and hypospadias.

  • Cri du Chat Syndrome:

    • Deleted Region: 5p

    • Clinical Features: Mental and growth retardation, characteristic high-pitched cat-like cry in infancy, microcephaly, round face, hypertelorism, and down-slanting palpebral fissures.

  • Sotos Syndrome:

    • Deleted Region: 5q35

    • Clinical Features: Intellectual disability, overgrowth, long thin facies with a broad forehead, sparse frontoparietal hair, down-slanted palpebral fissures, macrocephaly, advanced bone age, behavior problems, hypotonia, feeding problems, renal anomalies, scoliosis, and seizures.

  • Williams Syndrome:

    • Deleted Region: 7q11.23

    • Clinical Features: Mental retardation, short stature, supravalvular aortic stenosis, hypercalcemia, overly friendly disposition, hoarse voice, periorbital fullness, stellate pattern in the iris, anteverted nares, long philtrum, and full lips.

  • Potocki-Shaffer Syndrome:

    • Deleted Region: 11p11.2

    • Clinical Features: Mental retardation, biparietal foramina, brachycephaly, turricephaly, multiple exostoses, micropenis, and minor facial dysmorphism (high forehead, small upturned nose with broad tip, downturned mouth).

  • Jacobsen Syndrome:

    • Deleted Region: 11q24.1–11qter

    • Clinical Features: Mental and growth retardation, trigonocephaly, strabismus, cardiac defects, digit anomalies, and thrombocytopenia.

  • Langer-Giedion Syndrome:

    • Deleted Region: 8q24.11–8q24.13

    • Clinical Features: Mental and growth retardation, multiple exostoses, cone-shaped epiphyses, fine scalp hair, bulbous nose, prominent ears, simple but prominent philtrum, and loose redundant skin in infancy.

  • Angelman Syndrome:

    • Deleted Region: Maternal 15q11.2–15q13.1 deletion (complementary to the 15q11.2–15q13.1 microduplication region).

    • Clinical Features: Mental and growth retardation, frequent unprovoked laughter, ataxia with jerky arm movements, seizures, maxillary hypoplasia, deep-set eyes, large mouth with protruding tongue, widely spaced teeth, and prognathia.

  • Prader-Willi Syndrome:

    • Deleted Region: Paternal 15q11.2–15q13.1

    • Clinical Features: Mental and growth retardation, hypotonia and severe feeding problems in infancy, hyperphagia leading to obesity later in life, narrow bifrontal diameter, almond-shaped eyes, small hands and feet, hypogonadism, and compulsive skin picking.

  • 15q13.3 Microdeletion:

    • Deleted Region: 15q13.3

    • Clinical Features: Developmental delay with mild to moderate learning disability, autism spectrum disorder, schizophrenia, epilepsy, seizures, digit anomalies, and facial features including hypertelorism, short philtrum, and a thick, everted upper lip. Shows extensive phenotypic variability and incomplete penetrance.

  • Rubinstein-Taybi Syndrome:

    • Deleted Region: 16p13.3

    • Clinical Features: Mental retardation, postnatal growth retardation, hypotonia, broad thumbs and broad big toes, cryptorchidism, downward-slanting palpebral fissures, heavy highly arched eyebrows, long eyelashes, prominent or beaked nose, and hypoplastic maxilla with a narrow palate.

  • Miller-Dieker Syndrome:

    • Deleted Region: 17p13.3

    • Clinical Features: Mental and growth retardation, lissencephaly, microcephaly, bitemporal depression, long philtrum, thin upper lip, mild micrognathia, ear dysplasia, and anteverted nostrils.

  • Hereditary Neuropathy with Liability to Pressure Palsies (HNPP):

    • Deleted Region: 17p11.2 deletion (complementary to the Charcot-Marie-Tooth 1A duplication).

    • Clinical Features: Asymmetric recurrent palsies precipitated by focal pressure starting in the second or third decade of life; electrophysiologic studies demonstrate prolonged sensory motor nerve conduction.

  • Smith-Magenis Syndrome:

    • Deleted Region: 17p11.2

    • Clinical Features: Mental retardation, behavioral problems, hyperactivity, severe sleep disturbance, decreased pain sensitivity, short stature, brachycephaly, midface hypoplasia, prognathism, prominent fingertip pads, and hoarse voice.

  • 17q21.3 Microdeletion:

    • Deleted Region: 17q21.3 (complementary to the 17q21.2 microduplication region).

    • Clinical Features: Mental retardation/developmental delay, speech delay, friendly disposition, hypotonia, normal growth, epilepsy, heart anomalies, renal/urologic anomalies, abnormal hair color or texture, and typical facies (high broad forehead, ptosis, blepharophimosis, up-slanting palpebral fissures, epicanthal folds, tubular- or pear-shaped nose, prominent ears).

  • Alagille Syndrome:

    • Deleted Region: 20p12.2

    • Clinical Features: Cholestasis, peripheral pulmonic stenosis, vertebral arch defects, posterior embryotoxon, and facial features including deep-set eyes, broad forehead, long straight nose, prominent chin, and small low-set or malformed ears.

  • DiGeorge Syndrome:

    • Deleted Region: 22q11.2 deletion (complementary to the proximal 22q11.2 microduplication region).

    • Clinical Features: Learning disabilities, short stature, overt or submucous cleft palate, velopharyngeal incompetence, prominent nose with a squared nasal root and narrow alar base, conotruncal cardiac defects, and psychiatric disorders in some individuals.

  • Phelan-McDermid Syndrome:

    • Deleted Region: 22q13.3

    • Clinical Features: Moderate to severe developmental delay, severe expressive speech delay, behavior disturbance, increased pain tolerance, hypotonia, normal to accelerated growth, dysplastic toenails, large hands, and minor facial dysmorphisms (dolichocephaly, ptosis, abnormal ears, pointed chin).

  • Kallmann Syndrome:

    • Deleted Region: Xp22.3

    • Clinical Features: Hypogonadotropic hypogonadism, eunuchoid habitus (a physical disposition also characteristic of Klinefelter syndrome), anosmia or hyposmia, and bimanual synkinesis.

  • X-Linked Ichthyosis:

    • Deleted Region: Xp22.3

    • Clinical Features: Hypertrophic ichthyosis and corneal opacities occurring without vision impairment.

Chromosomal Duplications

  • Definition:

    • The presence of an extra copy of a genomic segment, resulting in partial trisomy.

    • Can occur as an isolated pure duplication or in combination with a deletion or other structural rearrangement.

  • Types of Duplications:

    • Tandem Duplication: The duplicated genomic section is directly adjacent to the original sequence.

    • Displaced Duplication: The duplicated section is separated from the original region by non-duplicated genomic sequences.

Duplication Syndromes and Clinical Features

  • Duplication 3q:

    • Duplicated Region: 3q26.3

    • Clinical Features: Cornelia de Lange-like phenotype including mental retardation, postnatal growth retardation, long philtrum, palate anomalies, anteverted nares, clinodactyly, talipes, and renal and cardiac abnormalities.

  • 7q11.23 Microduplication:

    • Duplicated Region: 7q11.23 duplication (complementary to the 17q21.2 microdeletion region).

    • Clinical Features: Variable cognitive abilities ranging from normal intelligence to moderate mental retardation, with speech delay present in all patients; autism, hypotonia, heart defects, diaphragmatic hernia, cryptorchidism, short philtrum, thin lips, and straight eyebrows.

  • Beckwith-Wiedemann Syndrome:

    • Duplicated Region: Paternal 11p15.5

    • Clinical Features: Macrosomia, macroglossia, organomegaly, omphalocele, ear creases, hypoglycemia, and tumor susceptibility. Patients with cytogenetic duplications are significantly more likely to display learning difficulties.

  • Pallister-Killian Syndrome:

    • Duplicated Region: Mosaic tetrasomy 12p (usually secondary to an extra metacentric isochromosome).

    • Clinical Features: Mental retardation, hyper- and hypopigmented skin streaks, sparse anterior scalp hair, sparse eyebrows and eyelashes, prominent forehead, protruding lower lip, and facial coarsening over time.

  • Proximal 15q11.2 Microduplication:

    • Duplicated Region: 15q11.2–15q13.1 (complementary to the Prader-Willi/Angelman deletion region).

    • Clinical Features: Mild to severe intellectual impairment (especially affecting language), autism spectrum disorders, reduced motor coordination, hypotonia, reduced deep tendon reflexes, joint laxity, and mild or absent dysmorphic features. Associated predominantly with maternal duplications.

  • **Pseudodicentric 15 (