Imprinting

Imprinting is the process by which maternally and paternally derived chromosomes are uniquely chemically modified (usually by methylation), leading to different expression of a certain gene or genes on those chromosomes depending on their parental origin. Patterns of gene expression and repression of gene expression vary between imprinted regions.

Methylation, the attachment of methyl groups to DNA at cytosine bases, is correlated with reduced transcription of a gene and is thought to be the principal mechanism of imprinting. An assay designed to detect the methylation pattern at a specific chromosome locus (e.g., methylation-sensitive multiplex ligation probe analysis [MS-MLPA], methylation-sensitive quantitative PCR [MS-qPCR], Southern blotting) is necessary to identify epigenetic imprinting errors. Sequencing techniques including next-generation sequencing used in exome sequencing and genome sequencing do not identify methylation patterns.

Uniparental Disomy

Uniparental disomy (UPD) is the situation in which both members of a chromosome pair or segments of a chromosome pair are inherited from one parent and neither is inherited from the other parent; uniparental disomy can result in an abnormal phenotype if genes within the chromosome segment are imprinted.

The ability of sequence analysis to identify UPD by sequencing DNA from the proband alone depends on the type: uniparental isodisomy versus uniparental heterodisomy.

• Uniparental isodisomy (i.e., two copies of a single chromosome or chromosome segment are inherited from one parent and no copy is inherited from the other parent) may be identified by long stretches of homozygosity by sequencing techniques; however, further testing (e.g., chromosomal microarray analysis) may be required to distinguish a deletion from uniparental isodisomy.
• Uniparental heterodisomy (i.e., both chromosomes of a chromosome pair or chromosome segment are inherited from one parent and no copy is inherited from the other parent) cannot be identified by sequencing techniques unless recombination has reduced regions of the chromosome to homozygosity. Other test methods such as methylation studies or parental testing (e.g., short tandem repeat (STR) analysis or SNP array) are required to identify uniparental heterodisomy.

The table below provides a list of disorders caused by imprinting errors and UPD organized by chromosome locus.

References

• Kearney HM, Kearney JB, Conlin LK. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med. 2011;31:595–613. [PubMed: 22118739]
• Mulchandani S, Bhoj EJ, Luo M, Powell-Hamilton N, Jenny K, Gripp KW, Elbracht M, Eggermann T, Turner CL, Temple IK, Mackay DJ, Dubbs H, Stevenson DA, Slattery L, Zackai EH, Spinner NB, Krantz ID, Conlin LK. Maternal uniparental disomy of chromosome 20: a novel imprinting disorder of growth failure. Genet Med. 2016;18:309–15. [PubMed: 26248010]
• Scott RH, Douglas J, Baskcomb L, Huxter N, Barker K, Hanks S, Craft A, Gerrard M, Kohler JA, Levitt GA, Picton S, Pizer B, Ronghe MD, Williams D., Factors Associated with Childhood Tumours (FACT) Collaboration. Cook JA, Pujol P, Maher ER, Birch JM, Stiller CA, Pritchard-Jones K, Rahman N. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nat Genet. 2008;40:1329–34. [PubMed: 18836444]
• Shuman C, Smith AC, Steele L, Ray PN, Clericuzio C, Zackai E, Parisi MA, Meadows AT, Kelly T, Tichauer D, Squire JA, Sadowski P, Weksberg R. Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies. Am J Med Genet A. 2006;140:1497–503. [PubMed: 16770802]
• Soellner L, Begemann M, Mackay DJ, Grønskov K, Tümer Z, Maher ER, Temple IK, Monk D, Riccio A, Linglart A, Netchine I, Eggermann T. Recent advances in imprinting disorders. Clin Genet. 2017;91:3–13. [PubMed: 27363536]
• Takatani R, Minagawa M, Molinaro A, Reyes M, Kinoshita K, Takatani T, Kazukawa I, Nagatsuma M, Kashimada K, Sato K, Matsushita K, Nomura F, Shimojo N, Jüppner H. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B). Bone. 2015;79:15–20. [PMC free article: PMC4501871] [PubMed: 25997889]