Uniparental disomy

Uniparental Disomy

non traditional inheritance pattern where 2 copies of ch or part of ch is inherited from single parent

Uniparental disomy phenotypic differences when

chromosome involves genes that are imprinted

genes express autosomal recessive condition

Concept of UPD first introduced

Engel 1980

first case of UPD in humans documented

1988

child with CF

Strategies for detecting UPD

examine individuals with more than one recessive disorder

investigate patients lacking a deletion

focus on chromosomes with imprinted genes

examine individuals with apparent balanced translocations or other ch rearr

pinpoint ch most often involved in germ cell aneuploidies

UPD Cytogenetic warnings

in prenatal samples mosaicism

translocation (mostly robertsonian)

inversion, pericentric or paracentric

unusual heteromorphic chromosomal pattern

in parental students knowing of parents translocation or inversion

Trisomic rescue

ch loss in trisomy forming disomic fetus

most common mechanism of UPD

each ch has equal chance being lost

2/3 chance normal genotype

1/3 chance of UPD

gametic complementation

fusion of two gametes where both are abnormal

thought to be rare

monosomic rescue

one ch from gamete duplicated to restore euploidy

duplication of ch

often seen with isodisomy formation

must occur soon after fertilization

cells are isodisomic

segmental udp

somatic recombination where exchange region is imprinted

Maternal UPD

more common since nondisjunction occurs more frequently in oogenesis

Associated disorders

angelman syndrome, prader-willi, beckwith0wiedemann, silver-russel, maternal upd ch 14

isolated cases with upd

all ch except 12, 17, 18, 19, Y

Overall frequency of UPD

unknown if abnormal genes not involved may go undetected

udp can be found in normal children

if genes are imprinted

udp can go undetected until se x of individual changes

Structural abnormalities leads to

higher risk of UPD robersonian translocations 0.6-0.9%

homologous acrocentric rearrangements 66%

Detection of UPD is done using

PCR

FISH analysis will only detect

deletions

imprinting

differential expression of alleles as determined by the parental origin of the allele

Methylation

modifies genes in germ cells

genes from one parent are silenced imprinted gene not expressed

The imprint switch theory

theory on how imprinting works

DNA sequence called imprint center helps set and reset imprint

imprinted genes do not switch their expression patterns unless IC signal received

once IC signal is transmitted it will switch its own imprint

Errors that can occur with imprint switch

if mutation or deletion occurs in IC it will block the imprint

this can be passed down generations

15q11-q13 region

imprint center includes SNRPN promoter

SNRPN gene has elements for IC

Prader willi

ch 15 UPD Maternal

occurance 1/15,000

Angelman

paternal upd ch 15

1/15,000

Beckwith-wiedemann

paternal upd ch 11

1/13,700

temple syndrome

maternal upd ch 14

Prader willi gene

maternal upd ch 15 15q11-13

genes SNRPN and ZNF127

Prader willi clinical features

short stature, small hands and feet, truncal obesity, behavior problems, dysmorphic features

Angelman syndrome location and gene

paternal upd ch 15

15q11-13

unknown candidate gene

angelman syndrom clinical features

severe mental retardation, seizures, wide mouth, lack of speech, inappropriate laughter, ataxic gait, hand flipping, jerky movements, very happy easy excitability, sleeping and eating problems.

Beckwith-wiedemann gene and location

mapped to 11p15.5

IGF2 H19

Beckwith-Wiedemann clinical features

macroglossia (enlarged tongue), gigantism, organomegaly, abdominal wall defects, ear creases, renal abnormalities, predisposition for developing wilms tumor

Silver russell syndrome

Maternal upd ch 6 candidate gene unknown

Silver russell syndrome clinical features

low birth weight intrauterine growth retardation, short stature, triangular face, scaphocephaly, normal head size appearing large due to body, fifth finger clinodactyly, poor appetite, developmental delays

Maternal UPD ch 14

14q22

candidate genes DLK1 and GTL2 genes

Maternal UPD ch 14 clinical features

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

Uniparental disomy could exist in

heterodisomy, isodisomy, segmental/partial disomy

G band analysis can detect UPD

false

Chance of trisomic rescue resulting in normal genotype

66%

Imprinted gene is considered

silenced and not expressed.