Genomic Imprinting

Med Gen exam 2

What chromosomes can be imprinted

6,7,11, 14,15, and 20

What is genomic imprinting

Normal expression or non-expression of genes in a parent-of-origin specific manner ex. Maternal or paternal inheritance

How are imprinted genes silenced usually

Methylation

What is a paternally imprinted gene

Paternally silenced gene

What is a maternally imprinted gene

Maternally silenced gene

What is the evidence of imprinting

Pronucelar transplantation, human triploids, uniparental chromosomal disomies, chromosome deficiency in mice and humans, analysis of transgene expression, expression of specific genes

What is gynogenetic in pro nuclear transplantation

Only maternal chromosomes are used in formation

Characteristics of gynogenetic in pronuclear transplantation

Poor development of membranes and placentas, good embryonic development, and ovarian teratomas

What is androgenetic in pronuclear transplantation

Only paternal chromosomes used

What are the characteristics of androgenetic pronuclear transplantation

Normal development of membranes and placenta, poor development of embryonic structures, and complete mole

Characteristics of genomic human triploids

Underdeveloped placenta without cystic changes, severe asymmetric IUGR probably due to placental insufficiency, large head

Characteristics of Diandry or Android human triploids

Large cystic placenta, poor survival only due to mosaicism, well grown to symmetric IUGR, normal or microcephalic

What are shared features of triploids

Dysplasia calvaria with large posterior fontanelle, ¾ finger syndactyly, cardiac defects ASD and VAD, hydrocephalus, holoprosencephaly

Why might triploids be missed on NIPT

Low hCG and no elevated ratios so cannot compare to reference

What can disruption of genomic imprinting cause

Uniparental disomy, imprinting center defects, chromosomal/single gene deletions

What are the 3 proposed mechanisms of uniparental disomy

Trisomy rescue, monosomy rescue, gamete complementation

What is uniparental isodisomy

Uniparental disomy involving the same chromosome

What is uniparental heterodisomy

Uniparental disomy of 2 different chromosomes

What are the possible consequences of trisomy rescue

Uniparental isodisomy or heterodisomy

What are the possible consequences of monosomy rescue

Uniparental isodisomy only

What is gamete complementation of UPD

Meiosis errors that occur at the same time in both parents

Possible consequence of gamete complementation

Uniparental heterodisomy or isodisomy depending on where meitotic error occurs

What are the possible consequences of UPD

No consequence (not all chromosomes imprinted), uncovers an autosomal recessive condition, chromosome carries an imprinted gene

What is imprinting center

Controls methylation pattern during oogenesis/spermatogenesis

What happens when the imprinting center does not work

Switch in sex-specific methylation pattern does not occur, sperm with maternally imprinted genes or eggs with paternally imprinted genes

Which tissues have a greater number of imprinted genes

Placenta and brain tissues

What are the imprinting disorders we discussed in class

Beckwith-Weidemann/Russel-Silver, Prader-Willi/Angelman syndrome, Kagami-Ogata/Temple syndrome, Albright hereditary osteodystrophy

Where is BWS and RSS locus

Chromosome 7 11p15.5

What are BWS tier 1 findings

Macroglossia, omphalocele/exomphalos, embryonal tumor like Wilma tumor, hepatoblastoma, or nephroblastomatosis, hemihyperplasia of one or more body segments, cytomegaly of adrenal cortex, macrosomnia

What are BWS tier 2 findings

Visceromegaly, unilateral or bilateral earlobe creases and/or posteriors helical ear pits, macroglossia, infraorbital creases, mid face recursion, thin vermillion of upper lip, prominent jaw, cleft palate, kidney anomalies, umbilical hernia, embryonal tumors, transient hypoglycemia

What are BWS tier 3 findings

Supportive of diagnosis in presence of their 1 and 2 findings, small umbilical hernia or diastasis recti, polyhydramnios and or placenta metals, premature birth, negus simplex and or hemangioma, isolated transient hypoglycemia, structural cardiac anomalies or cardiomegaly,

What is required for a diagnosis of BWS

4 points, 2 tier 1 findings, one tier 1 and two tier 2 findings

Prevalence of BWS

1 in 10,00-13,000

What are the genetic mechanisms behind BWS

Loss of methylation on imprinting center 2 on maternal chromosome, gain of methylation of imprinting center 1 on maternal chromosome, mutation in CDKN1C allele, paternal uniparental disomy of chromosome 7, cytogenetic translocation, inversion, or duplication, unknown

What is the main genetic mechanism of BWS

Loss of methylation on imprinting center 2 on maternal chromosome

What is the typical imprinting of imprinting centers on chromosome 7

Imprinting center 1 paternally imprinted, imprinting center 2 maternally imprinted

What does normal imprinting on imprinting center 1 on chromosome 7 cause

Interaction of enhancer with IGF2 gene to allow transcription on paternal chromosome, methylation of imprinting center 2 on maternal chromosome allows expression of KCNQ1 and CDKN1C

What dies loss of methylation on imprinting center 2 on maternal chromosome cause BWS

Downregulated CDKN1C which is a growth inhibitor, CDKN1C maternally expressed

What does methylation on imprinting center 1 on maternal chromosome cause in BWS

Overexpression of IGF2 since maternally not expressed through lack of methylation

What does mutation of maternal CDKN1C allele cause in BWS

Underexpression of CDKN1C growth restrictor

What does paternal uniparental disomy cause BWS

Double whammy, overexpression of IGF2 and underexpression of CDKN1C

What is the testing strategy for BWS

DNA methylation, CDKN1C sequencing analysis, Chromosomes and CMA

What is the recurrence for BWS if there is UPD

Less than 1%

What is the recurrence risk of BWS in CDKN1C defects

Up to 50%

What is the surveillance for BWS

Neonatal hypoglycemia, abdominal ultrasound every 3 months until 8, annual renal ultrasound from age 8 until mid adolescence, AFP every 3 months until age 4, urinary calcium/creatine every 6-12 months

What is the genotype of BWS when neoplasia is found

UPD, CDKN1C defects, imprinting center 2 loss (rare)

What is the genotype when family history of BWS present

CDKN1C defects, del/dup of 11p15.5

What is the genotype of BWS when cleft palate found

CDKN1C defects

What is the genotype of BWS when omphalocele found

CDKN1C defects, imprinting center 2 alterations

What are the clinical criteria (4 of 6 findings) of Russel-Silver syndrome

Small for gestational age, postnatal growth failure, relative macrocephaly, frontal bossing or prominent forehead, body asymmetry, feeding difficulties

Supportive findings of Russell-Silver syndrome

Delayed closure of anterior fontanelle, triangular face, micrognathia, dental crowding, down turned corners of mouth, high pitched voice, diminished muscle mass, shoulder dimples, hypoplastic elbow joints, fifth finger clindactyly and or brachydactyly, scoliosis, excessive sweating, fasting hypoglycemia, speech and motor delay, genitourinary anomalies

What is surveillance like for Russel-Silver syndrome

Screening for malformation and developmental delay, growth hormone, hypoglycemia

Incidence of Russel-Silver syndrome

1 in 30,000-100,000

What are the genetic mechanisms of Russell-Silver Syndrome

Loss of paternal imprinting center 1 methylation, maternal 11p15.5 duplication, chromosome 7 del/dup, unimaternal disomy chromosome 7

What does loss of imprinting on imprinting center 1 on paternal chromosome 7 cause RSS

Enhancer unable to interact with IGF2 to activate, underexpression of IGF2

What does duplication of maternal 11p15.5 cause RSS

Overexpression of CDKN1C growth repressor

What is the testing strategy for RSS

DNA methylation, Chromosome 7 UPD studies, CMA, consideration of mosaicism or clinical dx

What is the recurrence risk of RSS when UPD of chromosome 7 occurs

Low

What region is Angelman and Prader-Willi found in

Chromosome 15, 15q11-q13

What causes Prader-Willi syndrome

Loss of paternally expressed genes at 15q11-q13

What is the prevalence of PWS

1 in 10,000-30,000

What are the features of PWS

Decreased fetal movements, hypotonia, hyperplasia, almond shaped eyes, downturned mouth, thin upper lip, small hands and feet, skin picking, growth hormone deficiency, hypogonadism, ID

What are the genetic etiologies as PWS

Paternal deletion of 15q11-q13, maternal UPD, imprinting center defect, most cases de novo

What is the recurrence risk for imprinting center defects in PWS

50%

How can imprinting center defects be passed through a family with PWS

PWS can only be inherited when imprinting center defects are passed on from father

What is the testing strategy for PWS

DNA methylation, CMA, FISH/Karyotype, IC deletion

Recurrence risk of PWS when paternal deletion, unimaternal disomy, IC mutation, normal chromosomes

Less than 1%

Recurrence risk of PWS when translocation or IC deletion

Up to 50%

Recurrence risk of PWS when unimaternal disomy of 15, translocation, or marker chromosome

Theoretically as high as 100%

What causes Angelman syndrome

Loss of maternal UBE3A gene expression, 15q11.2-q13

What is the prevalence of Angelman syndrome

1 in 12,000-20,000

What are the features of Angelman syndrome

Long philtrum, prominent lower lip, small, widely spaced teeth, wide mouth, postnatal microcephaly, severe-profound ID, severe speech impairment, spasticity and half-flapping, apparent happy demeanor

What is they typical presentation in Angelman Syndrome

Normal prenatal and birth history, normal head circumference at birth, structurally normal brain on MRI, delayed milestones, slow head growth with microcephaly by age 2, seizures by age 3 abnormal EEG

What are the genetic etiologies of Angelman Syndrome

Uniparental disomy, imprinting center defects, deletions, pathogenic variants

What is the recurrence risk of AS in UBE3A pathogenic variants and imprinting center defects

Up to 50%

What is the recurrence risk of AS in de novo cases

Less than 1%

How can AS be passed down in a family

Affected children only come from carrier moms of UBE3 mutation

What is the testing strategy for AS

DNA methylation, CMA, FISH/Karyotype, UBE3 sequencing

Where is Kagami-Ogata Syndrome and Temple syndrome located

Chromosome 14n q32.2 region

What are the obstetric complications for the mother in Kagami-Ogata Syndrome

Polyhydramnios, premature labor, large placenta

What causes Kagami-Ogata Syndrome

Unipaternal disomy of chromosome 14, maternal microdeletion, epimutation

What are the features of KOS

Bell-shaped thorax at 23 weeks, coat hanger ribs, growth restriction, obesity, severe DD, delayed bone marrow, full cheeks, protruding philtrum, abdominal wall defects

What causes KOS

Loss of maternally expressed genes on chromosome 14

What causes Temple syndrome

Loss of paternally expressed genes on chromosome 14

What are the features of Temple syndrome

Prenatal and postnatal growth restriction, hypotonia, joint laxity, motor delay, normal IQ, early onset of puberty, minor dysmorphic features of face, hands, and feet

What causes Temple syndrome

Maternal UPD

What is the testing strategy for chromosome 14 UPD

DNA methylation, CMA, chromosome analysis to rule out 14:14 translocation

What are the features of Albright Hereditary Osteodysthrophy

Early onset obesity, round face, short stature, short 4-5 metacarpals, short 4-5 metatarsals, skin calcifications

What is the function of GNAS in paternal chromosomes

Skeletal system

What is the function of GNAS in maternal chromosomes

Endocrine, and skeletal system

What is pseudo-pseudo-hypoparathyroidism

AHO with no endocrine abnormalities

What is pseudo-hypoparathyroidism 1A

AHO plus endocrine abnormalities, TSH resistance, Lh/FSH resistance, GhRH resistance, PTH resistance

What other disorders is imprinting present in

Transient neonatal diabetes mellitus (TNDM), Pheochromocytoma/Paraganglioma, Neuroblastoma, Retinoblastoma

What is ART

Assisted Reproductive Technology, any in vitro manipulation of embryos for establishing pregnancy

What does ART include

IVF, Embryo transfer, gamete intrafallopian transfer, zygote intrafallopian transfer, tubal embryo transfer, gamete and embryo cryopreservation, oocyte and embryo donation, gestational surrogacy

What does ART not include

Artificial insemination using donor sperm

What is an implication of ART

Implications associated with imprinting disorders

Why can ART interfere with imprinting disorders

Possibly due to embryonic manipulations and ovarian stimulations, intracytoplasmic sperm injection leading to hypomethylation