STEPTRACKERGENETICS + NEUROLOGY | IMPRINTING & REPEATS | HIGH-YIELD REVIEW

Imprinting & Trinucleotide Repeats

Two families of "unusual" inheritance: which parent passed it matters (imprinting), and the gene gets longer and worse each generation (repeats).

FOCUS ON

Chromosome 15q11–q13: Prader-Willi = loss of paternal genes (maternal ones are normally silenced) — deletion or maternal UPD. Angelman = loss of maternal UBE3A — deletion or paternal UPD. Repeats: Huntington CAG (paternal anticipation), myotonic dystrophy CTG, fragile X CGG and Friedreich GAA (AR).

DISORDER

GENETICS

FEATURES

CLUE

Prader-Willi syndrome

Paternal 15q11–q13 lost: paternal deletion (~70%) or maternal uniparental disomy (~25%); maternal copy imprinted (silent)

Neonatal hypotonia, poor feeding → later hyperphagia, obesity, hypogonadism, small hands/feet, mild ID, behavior problems

"Father lost → Prader"

Angelman syndrome

Maternal UBE3A lost: maternal deletion or paternal UPD or UBE3A mutation

Happy puppet: inappropriate laughter, ataxic gait, seizures, severe ID, absent speech

"Mother lost → Angelman (UBE3A)"

Beckwith-Wiedemann

11p15 imprinting

↑ IGF2 expression (paternal UPD or methylation defect)

Macrosomia, macroglossia, hemihyperplasia, omphalocele, neonatal hypoglycemia

Wilms tumor and hepatoblastoma risk

Huntington disease

AD · CAG · ch 4

Polyglutamine huntingtin; > 36 repeats; expands in paternal transmission

Chorea, depression, dementia, onset 30s–50s; caudate atrophy

↓ GABA, ↓ ACh, ↑ dopamine

Myotonic dystrophy type 1

AD · CTG · DMPK

Expands in maternal transmission (congenital form)

Myotonia (can't release grip), cataracts, frontal balding, testicular atrophy, arrhythmias, distal weakness

Myotonia, cataracts, frontal balding, testicular atrophy

Fragile X syndrome

XD · CGG · FMR1

> 200 repeats → FMR1 hypermethylation → silenced; premutation expands in maternal transmission

ID, long face, large jaw, large ears, macroorchidism, hypermobility, autism, MVP

Most common inherited cause of ID

Fragile X premutation

55–200 repeats

Toxic RNA, not silencing

Premature ovarian insufficiency (women), tremor-ataxia syndrome (older men)

Grandfather's tremor, mother's early menopause

Friedreich ataxia

AR · GAA · frataxin

Impaired mitochondrial iron handling

Childhood ataxia, dorsal column/spinocerebellar loss, hypertrophic cardiomyopathy, diabetes, pes cavus, kyphoscoliosis

Leading cause of death: cardiomyopathy

Spinocerebellar ataxias

AD · CAG

Polyglutamine expansions in several genes

Adult-onset progressive ataxia

Anticipation

Picture it — chromosome 15 imprinting (teal = active paternal genes, purple = active maternal UBE3A)

NormalOne active paternal region and one active maternal UBE3A.

Prader-Willi — deletionPaternal region deleted; maternal copy is imprinted (silent).

Prader-Willi — maternal UPDTwo maternal chromosomes, no paternal genes.

Angelman — deletionMaternal UBE3A deleted; paternal copy is silent in neurons.

Angelman — paternal UPDTwo paternal chromosomes, no maternal UBE3A.

Schematic diagrams, not to scale.

Mechanism — which copy is active on 15q11–q13

Paternal copySNRPN etc. active; UBE3A silent in neurons

→

Lose paternalPrader-Willi

Maternal copyUBE3A active in neurons; SNRPN silent

→

Lose maternalAngelman

UPD flips it: two maternal copies = no active paternal genes (Prader-Willi); two paternal copies = no maternal UBE3A (Angelman).

Repeat disorders compared

DISEASE

REPEAT

INHERITANCE

EXPANDS VIA

Huntington

CAG

Father

Myotonic dystrophy

CTG

Mother

Fragile X

CGG

Mother

Friedreich

GAA

(no anticipation)

How it's tested

COMMON CONFUSIONPrader-Willi = missing paternal = maternal UPD. Angelman = missing maternal = paternal UPD. Say it in that order and it never flips.

THE TRAPFriedreich ataxia patients usually die of the heart (hypertrophic cardiomyopathy), not the ataxia.

YOUR APPROACHSame deletion, different phenotype → imprinting; earlier each generation → repeats; then identify the repeat by the organ pattern.

If you see… think…

Floppy newborn → insatiable eating and obesity → Prader-Willi

Inappropriate laughter, seizures, ataxia, no speech → Angelman

Prader-Willi with normal chromosomes on FISH → maternal uniparental disomy

Macroglossia, omphalocele, hemihyperplasia → Beckwith-Wiedemann

Chorea starting earlier in the son of an affected man → Huntington (paternal anticipation)

Can't let go of a handshake, cataracts, balding → myotonic dystrophy

Boy with ID, large ears, large testes → fragile X

Early menopause in a fragile X carrier mother → premutation

Teen with ataxia, pes cavus, hypertrophic cardiomyopathy → Friedreich (GAA)

Repeat that is autosomal recessive → GAA (Friedreich)