Imprinting and Uniparental Disomy

mechanisms and associated disorders

Imprinting mechanism

DNA methylation, post-translational histone modification, chromatin structure, noncoding RNAs (RNAi)

Uniparental disomy occurrence

can occur as a random event during the formation of egg or sperm cells or may happen early in fetal development, UPD for some chromosomes have no adverse effect on an individuals but can result in abnormality through aberrant genomic imprinting

UPD definition

two copies or parts of a chromosomes inherited from one parent

heterodisomy: same parental source, 2 chromosome

isodisomy: same parental source, same chromosome

When UPD is associated with phenotypic abnormalities

chromosome or chromosome segment involved carrier genes are imprinted

genes express autosomal recessive condition from a single carrier parent

CFTR gene location

chromosome 7

Cytogenetic warnings for UPD: Mosaic

aneuploid cell line with gain/loss of chromosome

not all mosaicisms have potential to become UPD

other UPD cytogenetic warnings

robertsonian translocation, inversion, unusual heteromorphic chromosomal pattern, knowledge of parental translocation/inversion

Trisomic rescue

lose trisomy —> become disomic

maternal upd more likely since nondisjunction happens more frequently in oogenesis

2/3 —> loss becomes normal phenotype

1/3 —> loss leads to UPD

Monosomic rescue

one chromosome from a normal gamete is duplicated when paired with nullisomic gamete to restore euploidy

dup can be mitotic or meiotic

often seen with isochromosome formation, needs to happen soon after fertilization

nondisjunction at meiosis II —> isodisomic

Gametic complementation

fusion of 2 particular gametes, both coincidentally abnormal, one nullisomic other disomic for same chromosome

rare, can expect heterodisomic and isodisomic lines

segmental UPD

somatic recombination where exchanged region is imprinted

UPD in Prader-Willi

Maternal 15q11-13, SNRPN and ZNF127

no mutations detected in specific gene, SNRPN methylated so not expressed since no paternal band

Prader-Willi molecular analysis

Absence of paternal alleles

maternal UPD also confirmed by inheritance of both copies of maternal 15 in child

UPD in Angelman

paternal 15q11-13, unknown gene

actual mutations detected in UBE3A, SNRPN not methylated and expressed

UPD in Silver-Russell Syndrome

chromosome 7, unknown genesS

Silver Russell Syndrome features

low birth rate d/t intrauterine growth retardation, short stature, triangular shaped face, scaphocephaly (long narrow head at birth), normal head size appearing large b/c reduced body length/weight, 5th finger clinodactyly (incurving), poor appetite, developmental delays

UPD in Beckwith-Wiedemann

paternal, 11p15.5 often segmental, candidate imprinted genes are IGF2(pat) and H19(mat)

Beckwith-Wiedemann Syndrome features

macroglossia (large tongue), giantism and organomegaly, abdominal wall defects, ear creases, renal abnormalities, predisposition for developing Wilms’ Tumor

Maternal UPD chromosome 14

14p32, include reciprocally imprinted DLK1 and GTL2 genes

Maternal UPD chromosome 14 features

low birth weight, developmental delay, precocious puberty, small hands, scoliosis, broad forehead, fleshy nasal tip, otitus media