Genomic Imprinting Flashcards
What is genomic imprinting?
For most genes, both copies are expressed
For some genes >>> either maternally or paternally derived copy is preferably used >>> this phenomenon is known as >>> Genomic imprinting
(imprinted = inactivated)
Examples of genomic imprinting
The best known:
Prader- Willi syndrome
Angelman syndrome
Others:
Albright’s hereditary osteodystrophy
Beckwith-Wiedeman syndrome
Russell Silver symdrome
Familial paraganglionoma
Which parental gene is deleted in Prader Willi syndrome?
Gene deleted from father
Which parental gene is deleted in Angelman syndrome?
Gene is deleted from mother
Cause of genomic imprinting in Prader Willi and Angelman syndrome
Either:
Cytogenetic microdeletions of the same region of chromosome 15 (long arm, q) OR
Uniparental disomy of chromosome 15
What is uniparental disomy?
Both copies of chromosome are derived from one parent
(NO copy from another parent)
Chromosomal and genetic abnormality in Prader Willi syndrome
70% cases: Microdeletion on Paternal (father) chromosome 15 OR
30% cases: Maternal uniparental disomy (= Both copies of chromosome 15 is derived from mother, none from father)
Many of remainder due to mutation in UBE3A gene chromosome 15 (q, long arm)
Chromosomal and genetic abnormality in Angelman syndrome
80% cases: deletion om maternal chromosome 15
2-3% paternal uniparental disomy ( = no maternal contribution)
Incidence of Prader Willi syndrome
1.2-1.3 per 10,000
Lifestyle of a Prader Willi patient
they can achieve high level of functioning to hold down simple part time job
But impossible for them to control appetite, to limit weight gain, or to limit food access
Body structure of Prader Willi syndrome
Short stature
Dysmorphic features
Hypotonia + obesity in late childhood
Limb features of Prader Willi syndrome
Small hand
Small feet
Incurred feet
Club foot
Congenital hip dislocation
Joint anomaly
Facial features of Prader-Willi syndrome
Squint
Almond shaped ears
Deafness
Cleft palate
Trunk features in Prader Willi syndrome
Asthma
Heart disease
Cor pulmonale
Gall stone
Duodenal ulcer
Bowel obstruction
Renal stone
Rectal prolapse
Scoliosis
Behavioural Changes in Prader Willi syndrome
Hyperphagia (starts 1 to 4years)
Moderate Learning difficulties
Behavioural problems in adolescent
Mental retardation
Self-injury
Reproductive features in Prader Willi syndrome
Small genitalia in male, female
Micropenis
Cryptorchidism
Hypogonadism
Infertility
Amenorrhoea in female
Skin problems in Prader Willi syndrome
Acanthosis nigricans
Boils
Hypothermia
Enodocrine disease in Prader Willi syndrome
Diabetes
Neonatal and childhood problems in Prader Willi syndrome
Neonatal: hypotonia + poor feeding
Childhood: Hyperphagia + obesity
Angelman syndrome: Behaviour
Happy puppet
Unprovoked laughter
Unprovoked clapping
Angelman syndrome: features in brain
Microcephaly
Severe learning disability
Seizures
Characteristic EEG
Angelman syndrome: Gait
Ataxia
Borad-based gait
Learning ability in Prader Willi syndrome and Angelman syndrome
Prader Willi syndrome: Moderate learning disability
Angelman syndrome: Severe learning disability
Albright’s hereditary osteodystrophy
Chromosome 20
Gene: GNAS
Encodes: alpha sub-unit of adenyl cyclase stimulating G-protein, Gs
Mutation deactivates GNAS gene
Genomic imprinting of Albright’s hereditary osteodystrophy
Mutation in maternally derived GNAS allele
Associated disease of Albright’s hereditary osteodystrophy
Pseudohypoparathyroidism
because it has the same gene mutation GNAS on chromosome 20
Stature and weight in Albright’s hereditary osteodystrophy
Short adult stature + tendency to obesity
Facial feature in Albright’s hereditary osteodystrophy
Round facies
Learning ability in Albright’s hereditary osteodystrophy
Mild-to-moderate learning disabilities
Bony feature in Albright’s hereditary osteodystrophy
- Brachydactyly:
Short metacarpals (particularly 4th and 5th)
Short distal phalanges (particularly thumb)
- Ectopic ossifications
Associated disease: pseudohypoparathyroidism also has short 4th and 5th metacarpals, as both are caused by GNAS gene mutation on chromosome 20
Beckwith-Wiedemann syndrome: Chromosome and gene (Genomic imprinting)
Chomosome 11
Gene: IGF2/ H19/ P57^kip/ KvLqQT1 gene cluster
Weight & size in Beckwith-Wiedemann syndrome
- Large birthweight
- Hemihypertrophy
Facial feature in Beckwith-Wiedemann syndrome
Facial nevus flammeus
Endocrine problem in Beckwith-Wiedemann syndrome
Neonatal hyperinsulinism >>> hypoglycaemia
Abdominal features in Beckwith-Wiedemann syndrome
- Omphalocele (Exomphalos)
- High risk of childhood abdominal tumours (particularly Wilm’s tumour and hepatoblastoma)
Russell-Silver syndrome: Genomic imprinting
In around 10% cases, maternal uniparental disomy for chromosome 7 + abnormalities of other imprinted regions
Onset of Russell-Silver syndrome
Prenatal onset
Prenatal features of Russell-Silver syndrome
Small stature + relative macrocephaly
Feeding in Russell-Silver syndrome
Very poor feeding
Bony features of Russell-Silver syndrome
Triangular face
Asymmetry
fifth finger clinodactyly
Main feature of Familial paraganglioma
Paragangliomas, including pheochromocytomas and glomus jugulare tumours occur throughout the body ( >> most common in the head and neck)
Familial paraganglioma: Genes
SDHB, SDHC, SDHD
Familial paraganglioms: Genomic imprinting
If a paerson carries mutated gene from mother >>> gets imprinted (=inactivated) >>> so, will not cause the disease
The mutation causes disease only when it is inherited from father
Familial paraganglioma: inheritence
Autosomal dominant
Each child has 50% has to be affected
But whether the mutant allele is expressed >> depends upon parental origin of the allele (whether mother/father)
