Uniparental Disomy
On this page
Direct answer
Two copies of chromosome 15, both inherited from the mother, with no deletion anywhere — this is uniparental disomy (UPD), the situation in which both members of a chromosome pair descend from a single parent, and it produces Prader-Willi syndrome because the paternally expressed genes on 15q are silenced on maternal copies. UPD matters through two distinct mechanisms: it disturbs imprinting (the same chromosome, wrong parental origin — Prader-Willi, Angelman, Beckwith-Wiedemann, Russell-Silver syndromes) and, when isodisomic, it renders the carrier homozygous for recessive alleles carried by one parent alone. The commonest route is trisomy rescue — a trisomic conception losing one chromosome to survive, and occasionally losing the only correctly inherited copy — which links UPD directly to the biology of miscarriage, chorionic villus mosaicism and apparently "unexplained" syndromes.
What you must remember
- Two forms: heterodisomy — both homologues from one parent (meiosis I nondisjunction, two different grandparental chromosomes); isodisomy — two copies of the same homologue (meiosis II error or post-zygotic duplication), which creates long stretches of homozygosity.
- Three routes of origin: trisomy rescue (commonest), monosomy rescue (duplication of the lone chromosome), and gamete complementation (a disomic gamete meets a nullisomic gamete for the same chromosome).
- Imprinting disorders caused by UPD: Prader-Willi from maternal UPD15 (about a quarter of Prader-Willi cases, the rest mostly deletions); Angelman from paternal UPD15 (a small fraction); Beckwith-Wiedemann from paternal UPD of 11p15 (roughly a fifth of cases); Russell-Silver from maternal UPD7 or 11p15.
- The isodisomy trap for recessive disease: a child with cystic fibrosis, congenital adrenal hyperplasia or spinal muscular atrophy born to a family where only one parent is a carrier can have inherited two identical mutant copies through isodisomy; UPD thus mimics autosomal recessive inheritance with a single carrier parent.
- Robertsonian translocation link: UPD of chromosomes 13, 14 and 15 can follow trisomy rescue in Robertsonian translocation carriers — a counselling connection between the two topics.
- Detection: methylation-specific studies (MS-MLPA) reveal the parent-of-origin pattern; single nucleotide polymorphism microarrays show long contiguous stretches of absence of heterozygosity flagging isodisomy; standard karyotype is normal — a point examiners emphasise.
- Recurrence risk: nearly always low when UPD arises sporadically after trisomy rescue, but parental translocation or mosaic UPD mandates individualised counselling.
Trisomy rescue, step by step
Walk the mechanism because every UPD fact hangs on it. Step one: maternal meiosis I nondisjunction produces an ovum with two maternal chromosome 15s; fertilisation adds the paternal copy — a trisomic conception that would miscarry. Step two: an early mitotic division ejects one of the three chromosomes at random; the embryo survives as a disomy. Step three: the gamble — one third of the time the cell discards the paternal copy, leaving two maternal copies, maternal UPD15; with imprinted, paternally expressed genes (the SNRPN cluster) silent on both copies, the baby has Prader-Willi syndrome despite a normal chromosome count.
The same rescue explains laboratory phenomena: a chorionic villus sample showing trisomy 15 mosaic in the placenta with a euploid fetus implies rescue occurred, and the fetus must then be checked for UPD. This chain — nondisjunction, trisomic conception, rescue, UPD — is the examinable sequence, and it converts imprinting from a memorised word into a mechanism.
Where the exam sets its traps
The deletion-negative Prader-Willi case is the classic trap: fluorescence in situ hybridisation for the 15q deletion is normal, and candidates stop; the answer is that maternal UPD and imprinting defects account for the deletion-negative majority, so methylation analysis — not repeated FISH — is the next test. Second, candidates forget that UPD requires the parent-of-origin to be wrong, not the gene sequence: the chromosomes may be entirely normal in sequence and dosage. Third, the isodisomy mechanism for recessive disease is under-quoted: a "one-carrier-parent" child with an autosomal recessive phenotype should prompt microarray analysis for homozygosity — elegant reasoning that distinguishes a postgraduate answer. Finally, do not promise recurrence risk of zero; trisomy rescue is sporadic, but maternal age and translocation contexts modify the counselling.
Frequently asked questions
What is the difference between heterodisomy and isodisomy?
Heterodisomy inherits both different homologues from one parent (meiosis I error), while isodisomy duplicates a single homologue, making the carrier homozygous across that region.
How does trisomy rescue generate uniparental disomy?
A trisomic conception loses one chromosome to survive; if the sole copy from the other parent is the one discarded, the remaining pair is uniparental.
Which syndrome results from maternal UPD of chromosome 15?
Prader-Willi syndrome, because the paternally expressed genes are silenced on both maternal copies — it is the commonest cause of deletion-negative Prader-Willi.
How can a child show autosomal recessive disease with only one carrier parent?
Isodisomy transmits two identical copies of the carrier parent's mutant allele, effectively making the child homozygous.
Which test detects uniparental disomy when the karyotype is normal?
Methylation-specific analysis such as MS-MLPA for imprinting disorders, and SNP microarray demonstrating absence of heterozygosity for isodisomy.