Chromosome Abnormalities
Overview
Chromosome abnormalities are among the most clinically frequent and most important genetic conditions to recognize. This chapter covers aneuploidies (abnormal chromosome number), microdeletion/microduplication syndromes (submicroscopic gains or losses detectable by CMA or FISH), and imprinting disorders (where gene expression depends on parent-of-origin).
Key concepts:
- Karyotype detects aneuploidies and large structural rearrangements (>5-10 Mb)
- Chromosomal microarray (CMA) detects smaller copy number variants (~50 kb–5 Mb)
- FISH provides rapid, targeted detection of specific regions
- Methylation studies are essential for imprinting disorders (PWS, AS, BWS, RSS)
- cfDNA screening has high sensitivity for common trisomies but is a SCREENING test
Key inheritance patterns:
- Most aneuploidies are sporadic (de novo nondisjunction)
- Microdeletions: ~90% de novo, ~10% inherited from a parent with the deletion
- Imprinting disorders: recurrence risk depends on mechanism (deletion vs UPD vs imprinting center defect)
Aneuploidy
Aneuploidy means an abnormal number of chromosomes, either extra (trisomy) or missing (monosomy). For each condition, the karyotype, key features, and recurrence risk are what matter. The autosomal trisomies (21, 18, 13) and sex chromosome aneuploidies (Turner, Klinefelter) are the most clinically important. Most autosomal trisomies result from maternal nondisjunction, and risk increases with maternal age.
Microdeletion syndromes
Microdeletions are submicroscopic chromosome deletions (typically 1-5 Mb) detected by CMA or FISH, not standard karyotype. Each syndrome involves loss of multiple contiguous genes. Most present with a core set of symptoms that includes:
- Growth deficiency
- Feeding difficulties
- Developmental delays or intellectual disability
- Craniofacial dysmorphism
- Multiple congenital anomalies (e.g. cardiac, renal)
The distinguishing features of each syndrome, along with the chromosomal region affected, are what set them apart. Most syndromes occur de novo (~90%), and so the recurrence risk is usually low. However, always consider testing parents for a balanced reciprocal translocations (particularly if the child has both a copy number loss on one chromosome and a copy number gain on another chromosome) since this may significantly affect the recurrence risk.
The mechanism by which recurrent deletions arise is also important. Non-allelic homologous recombination in meiosis causes recurrent de novo deletions that occur consistently in the same regions (e.g. 7q11.23, 22q11.2). In contrast, terminal microdeletion syndromes (e.g. 4p-, 5p-) have highly variable breakpoints.
Imprinting disorders
Imprinting is a normal phenomenon whereby gene expression at certain loci varies based on the parent of origin. Imprinting disorders occur when there is an imbalance of gene expression at at an imprinted locus. Therefore, the same genetic change (deletion, uniparental disomy) causes a different phenotype depending on whether the affected chromosome was maternal or paternal in origin.
Start by learning about Prader-Willi (loss of paternal 15q), and compare and contrast it with Angelman (loss of maternal 15q). This pair of disorders affects the same region, and the resulting disease depends on which allele (maternal or paternal) is affected. Then, compare and contrast Beckwith-Weidemann (overgrowth) with Russell Silver (undergrowth), as both involve an imbalance in gene expression at chromosome 11p15. Together, these are the 4 most important imprinting disorders to know.
For these disorders, knowing the molecular mechanisms of disease is important because different mechanisms carry widely different recurrence risks. The examples below illustrate this point. Here are a few examples to illustrate this with Angelman syndrome:
- paternal uniparental disomy: <1%
- maternally-inherited inherited UBE3A variant: 50%
- paternally-inherited 15;15 Robertsonian translocation: ~100%
You should also know which diagnostic test is most appropriate to send to confirm the diagnosis and identify the mechanism. Methylation testing is first line and confirms the diagnosis in most cases, though follow-up testing (e.g. chromosomal microarray, DNA sequencing) will help determine the exact mechanism. The GeneReviews pages for these conditions also have detailed diagnostic algorithms that are worth reviewing.
Chromosomal duplications
While deletions are more commonly encountered, duplications and tetrasomies also cause recognizable syndromes. These conditions often involve tissue mosaicism: the chromosomal abnormality may be present in some tissues (like skin) but not others (like blood), so the choice of tissue for testing matters. Pallister-Killian is the classic example: blood karyotype is often normal, requiring skin fibroblasts for diagnosis.
Mosaic aneuploidies
Mosaic aneuploidies, most commonly detected on prenatal CVS or amniocentesis, are a frequent counseling scenario. The key teaching point is confined placental mosaicism (CPM): the trisomic line lives in the trophoblast and the fetus has a normal karyotype. Trisomies 7, 16, and 20 account for most CPM. Confirmatory amniocentesis (which samples a different lineage than CVS) is the standard follow-up. True fetal mosaicism is much rarer and clinically variable; phenotype does not correlate well with the percentage of trisomic cells on amniocentesis because of tissue-specific distribution. A few mosaic aneuploidies (mosaic trisomy 8, 9) carry a recognizable postnatal phenotype.
Structural rearrangements
Structural rearrangements include isochromosomes, ring chromosomes, marker chromosomes, and balanced translocations/inversions. Isochromosome syndromes (e.g., i(12p) Pallister-Killian, i(18p) tetrasomy 18p, i(22q) cat eye) typically present as small supernumerary marker chromosomes (sSMCs) on karyotype with chromosomal microarray showing gain of the involved short arm. The mechanism is usually a maternal meiosis II error. Balanced rearrangement carriers are themselves phenotypically normal but carry meaningful reproductive risk for unbalanced offspring; partner karyotyping after a recurrent pregnancy loss workup is the standard counseling pathway.
Summary Table
| Disorder | Karyotype/Region | Inheritance | Cardinal Features | Key Test |
|---|---|---|---|---|
| Down syndrome | Trisomy 21 | Sporadic | Hypotonia, CHD (AVSD), characteristic facies | Karyotype |
| Edwards syndrome | Trisomy 18 | Sporadic | Clenched fists, rocker-bottom feet, CHD, lethal | Karyotype |
| Patau syndrome | Trisomy 13 | Sporadic | Holoprosencephaly, polydactyly, cleft, lethal | Karyotype |
| Triploidy | 69,XXX/XXY | Sporadic | Molar placenta (diandric) vs IUGR (digynic) | Karyotype |
| Turner syndrome | 45,X | Sporadic | Short stature, gonadal dysgenesis, coarctation | Karyotype |
| Klinefelter syndrome | 47,XXY | Sporadic | Tall, small testes, infertility, gynecomastia | Karyotype |
| Jacobs syndrome | 47,XYY | Sporadic | Tall stature, learning/speech delays, normal exam | Karyotype |
| Monosomy 1p36 | del 1p36 | ~80% de novo | Severe ID, seizures, LVNC, characteristic facies | CMA |
| Wolf-Hirschhorn | del 4p16.3 | ~90% de novo | Greek helmet facies, seizures, ID | CMA/FISH |
| Cri du chat | del 5p15 | ~85% de novo | Cat-like cry, microcephaly | CMA/FISH |
| Sotos syndrome | del 5q35 / NSD1 | ~95% de novo (AD) | Overgrowth, macrocephaly, advanced bone age, ID | CMA / NSD1 |
| Williams | del 7q11.23 | >99% de novo | SVAS, hypercalcemia, hypersocial | CMA/FISH |
| Langer-Giedion | del 8q24.1 (TRPS1/EXT1) | AD (de novo) | Sparse hair, bulbous nose, exostoses, cone epiphyses | CMA |
| WAGR | del 11p13 | Sporadic | Aniridia, Wilms tumor risk | CMA/FISH |
| Smith-Magenis | del 17p11.2 | ~95% de novo | Self-hugging, inverted sleep cycle | CMA/FISH |
| Potocki-Lupski | dup 17p11.2 (RAI1) | AD (de novo) | Hypotonia, FTT, ID, autism features, OSA | CMA |
| 22q11.2 deletion | del 22q11.2 | 90% de novo/10% AD | Conotruncal CHD, hypocalcemia, VPI | CMA/FISH |
| Prader-Willi | 15q11-q13 (pat) | See text | Neonatal hypotonia → hyperphagia/obesity | Methylation |
| Angelman | 15q11-q13 (mat) | See text | No speech, happy demeanor, seizures | Methylation |
| Beckwith-Wiedemann | 11p15.5 | Imprinting | Macrosomia, macroglossia, tumor risk | Methylation |
| Russell-Silver | 11p15/UPD7 | Imprinting | IUGR, triangular face, asymmetry | Methylation |
| Maternal 15q dup | dup 15q11.2-q13.1 (mat) | Sporadic | Autism, ID, refractory epilepsy, hypotonia | CMA |
| Cat eye syndrome | inv dup(22)(q11.2) | Sporadic | Iris coloboma, preauricular tags, anal atresia, CHD | Karyotype/FISH |
| Emanuel syndrome | +der(22)t(11;22) | Parental t(11;22) | Severe ID, micrognathia, ear tags, CHD, renal | Karyotype + CMA |
| Pallister-Killian | mosaic i(12p) | Sporadic | Coarse facies, sparse temporal hair, CDH, hypotonia | Fibroblast karyotype |
| Isochromosome 18p | i(18p) tetrasomy | De novo (mat) | ID, microcephaly, hypotonia → spasticity, seizures | Karyotype/FISH |
| Trisomy 20 mosaicism | +20 (CPM typical) | Sporadic | Usually CPM with normal fetus; rare TFM: IUGR, spinal/GU anomalies | Amnio karyotype |