Chromosomal Abnormalities & Microdeletion Syndromes

Numerical abnormalities and nondisjunction

Terms. Euploid cells carry exact multiples of the haploid set (46 in somatic cells). Aneuploidy is the gain or loss of single chromosomes (trisomy, monosomy); polyploidy adds whole sets, as in triploidy (69 chromosomes), which is almost never compatible with survival and is typical of a partial hydatidiform mole.

Meiotic nondisjunction. The commonest cause of aneuploidy is failure of chromosomes to separate at meiosis. Fertilization of a disomic gamete gives a trisomy; a nullisomic gamete gives a monosomy.

Maternal age. Oocytes enter meiosis I in fetal life and stay arrested in prophase I until ovulation, sometimes for more than four decades, while the cohesion holding homologs together erodes. About 90% of trisomy 21 is maternal in origin, mostly from meiosis I, and Down syndrome risk rises steeply after 35: roughly 1 in 350 at 35 and 1 in 100 at 40.

Mosaicism. A mitotic error after fertilization produces two cell lines; mosaicism also arises when a trisomic zygote loses the extra chromosome in only some cells (partial trisomy rescue). The phenotype is usually milder and variable, tracking the proportion of abnormal cells in each tissue, so a normal blood karyotype does not exclude it and another tissue, such as skin fibroblasts, may need testing.

Which aneuploidies survive. Only trisomies 13, 18 and 21 and the sex-chromosome aneuploidies reach live birth; 45,X is the only viable monosomy, and autosomal monosomies are lost very early. Trisomy 16 is the most frequent trisomy in first-trimester miscarriage and in its full, non-mosaic form is always lethal.

Down syndrome: three karyotypic routes

Why the route matters. Down syndrome affects roughly 1 in 700 live births. The phenotype is similar whatever the route, but recurrence risk is not. After a child with free trisomy 21, recurrence is about 1% or the mother's age-related risk, whichever is higher, and parental karyotypes are normal. When the child carries a translocation, both parents are karyotyped because one may be a balanced carrier; translocation Down syndrome is independent of maternal age.

Structural rearrangements

Robertsonian translocation. Two acrocentric chromosomes (13, 14, 15, 21 and 22, the D and G groups of the Denver classification) break at or near their centromeres and their long arms fuse. The short arms carry only redundant rRNA genes and are lost without harm, so a balanced carrier has 45 chromosomes and a normal phenotype. Robertsonian translocations are among the most common structural rearrangements in humans; t(13;14) is the most frequent.

Reproductive consequences. At the carrier's meiosis the fused chromosome and its two free partners segregate unevenly, so many gametes are unbalanced. Monosomic conceptions and most trisomic ones miscarry, causing recurrent pregnancy loss, but an extra 21q (or 13q) can be liveborn. A child with translocation Down syndrome has 46 chromosomes: two normal 21s plus a der(14;21) carrying a third 21q. For t(14;21), recurrence is about 10–15% when the mother is the carrier and only a few percent when the father is. A t(21;21) carrier makes only gametes with two copies of 21q or none; monosomy 21 is lost, so every liveborn child has Down syndrome.

Reciprocal translocation. Segments are exchanged between two nonhomologous chromosomes. With no net gain or loss the carrier is healthy, but at meiosis the four chromosomes pair as a quadrivalent and can yield unbalanced gametes carrying a partial trisomy plus a partial monosomy, leading to miscarriage or a malformed child. Acquired somatic translocations create fusion or deregulated oncogenes: t(9;22) BCR-ABL1 in chronic myeloid leukemia, t(8;14) MYC in Burkitt lymphoma, t(14;18) BCL2 in follicular lymphoma, t(15;17) PML-RARA in acute promyelocytic leukemia.

Isochromosome. When the centromere divides crosswise instead of lengthwise, each product has two identical arms, so one arm is duplicated and the other lost. i(Xq) is a Turner syndrome variant; i(12p) is the hallmark of testicular germ cell tumors; i(17q) appears in medulloblastoma and in CML progression.

Ring chromosome and inversion. Breaks near both tips let the broken ends join into a ring, deleting distal material; rings are unstable at mitosis, so mosaicism is common, and a ring X is another Turner variant. An inversion flips a segment within one chromosome (pericentric if it includes the centromere, paracentric if not); a pericentric inversion of chromosome 9 is a common harmless variant. Rings, isochromosomes and deletions are unbalanced, whereas translocations and inversions are usually balanced.

Uniparental disomy

Definition. In uniparental disomy (UPD) both copies of a chromosome, or of a segment, come from one parent while the count stays normal, so a standard karyotype looks normal.

Heterodisomy vs isodisomy. If the error arose in meiosis I, the retained pair is the parent's two different homologs (heterodisomy). If it arose in meiosis II, or a monosomic zygote duplicated its lone chromosome (monosomy rescue), the pair is identical (isodisomy). Crossing-over makes real cases patchy, partly iso- and partly heterodisomic.

Consequences. Isodisomy makes the child homozygous across that chromosome, so an autosomal recessive disease can appear when only one parent is a carrier; cystic fibrosis from maternal isodisomy 7 is the classic case. UPD of an imprinted region removes one parent's expressed genes: maternal UPD 15 causes Prader-Willi syndrome, paternal UPD 15 causes Angelman syndrome (as do UBE3A mutations), and paternal UPD of 11p15 causes Beckwith-Wiedemann syndrome. SNP microarrays reveal isodisomy as long runs of homozygosity; heterodisomy needs parental marker or methylation studies.

Detecting chromosomal abnormalities

Why the same deletions recur. Deletions at 7q11.23 and 22q11.2 arise by nonallelic homologous recombination between flanking low-copy repeats, so unrelated patients carry deletions of the same size.

Deletion and microdeletion syndromes

Cri-du-chat. The cat-like cry reflects laryngeal anomalies and fades with age. Most deletions are de novo; about 10–15% come from a parent carrying a balanced translocation. Do not confuse it with 4p deletion (Wolf-Hirschhorn syndrome), whose facies resemble a "Greek warrior helmet".

Williams syndrome. Loss of one elastin copy thickens and narrows large arteries, above all just above the aortic valve. Children are strikingly sociable and talkative despite intellectual disability, and hypercalcemia may appear in infancy.

22q11.2 deletion syndrome. The most common microdeletion, about 1 in 4,000 births. Loss of TBX1 and neighboring genes disrupts the 3rd pharyngeal pouch (thymus, inferior parathyroids), the 4th pouch (superior parathyroids) and neural-crest input to the cardiac outflow tract; Rathke pouch, by contrast, forms the anterior pituitary and is spared. Newborns may present with hypocalcemic tetany or seizures, an absent thymic shadow and T-cell deficiency ranging from mild to severe. Most deletions are de novo, but an affected adult transmits it with 50% risk. Diagnose with FISH or chromosomal microarray, since routine karyotyping usually misses it.

Hypercalcemia points to Williams; hypocalcemia points to the 22q11.2 deletion.

An infant with a 22q11.2 deletion and marked T-cell deficiency needs irradiated, CMV-negative blood products and no live vaccines until immune function is assessed; check calcium early, as seizures can be the first sign.