20. Microdeletions/microduplication syndromes Flashcards
What is the cause of Potocki-Lupski syndrome?
Duplication at 17p11.2 encompassing RAI1
How is Potocki-Lupski syndrome inherited?
Autosomal dominant, majority of cases are de novo
What is the clinical presentation of Potocki-Lupski syndrome?
Neurodevelopmental disorder:
- Dev delay, ID
- Hypotonia, dysphagia
- Communication disorder
- ADHD
Describe the mechanism the leads to the Potocki-Lupski syndrome/Smith-Magenis syndrome duplication/deletion
LCRs/segmental duplication on chr17p
NAHR occurs between LCRs flanking RAI1 –> recurrent CNV
Non-recurrent CNVs caused by fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR)
What is the cause of Smith-Magenis syndrome?
Deletion at 17p11.2 encompassing RAI1
What is the clinical presentation of Smith-Magenis syndrome?
Coarse facial features, dev delay, ID, failure to thrive, hypotonia
What is the cause of DiGeorge syndrome?
22q11.2 deletion
What are the major clinical manifestations of DiGeorge syndrome?
Congenital heart disease (Tetrology of Fallot, ventricular septal defect), cleft palate, LD, characteristic facies, hearing loss
What other genes can be impacted by 17q11.2 dels/dups?
FLCN - Birt-Hogg-Dube (hereditary cancer syndrome)
PMP22 - HMSN1A/HNPP
What is the main gene deleted in DiGeorge syndrome?
TBX1
What is the cause of Williams syndrome?
1.5- to 1.8-Mb deletion at 7q11
Mostly de novo
What is the clinical phenotype of Williams syndrome?
Mild ID, cardiovascular disease, elfin facial features, connective tissue abnormalities
What is the cause of the BP1-BP2 recurrent microdeletion?
15q11.2 deletion due to LCRs/NAHR
What is the clinical phenotype associated with BP1-BP2 microdeletion?
Susceptibility locus for neurodevelopment disorders such as dev delay
Low penetrance and variable expressivity
What are the key genes deleted in BP1-BP2 deletions?
NIPA1 and NIPA2
Which disorders are caused by deletions between the LCRs at 15q?
PWS/AS - deletion of BP1-BP3 or BP2-BP3
What is the phenotype of Emmanuel syndrome?
Multiple congenital abnormalities - microcephaly, cleft palate, congenital heart defects, kidney abnormalities
Pre- & postnatal growth deficiency
Hypotonia, severe developmental delay
What is the phenotype of Pallister-Killian syndrome?
Multiple congenital anomalies, seizures, severe developmental delay, macrosomia at birth, deafness, dysmorphic features
What causes Emmanuel syndrome?
Balanced t(11,22) in parent
Prone to 3:1 tertiary segregation
2x normal 11, 2x normal 22s + der 22 t(11,22)
What causes Pallister-Killian syndrome?
Supernumary iso(12p)
Mosaic, present in CVS, AF, fibroblasts, not in dividing lymphocytes
Results in tetrasomy of 12p
What phenotype is associated with 16p11.2 recurrent deletion?
Speech and language disorder, motor coordination difficulties, psychiatric conditions, autistic features, obesity
What causes 16p11.2 recurrent deletion?
NAHR due to LCRs
What is a contiguous gene syndrome?
A specific recognisable phenotype resulting from the loss or gain of multiple adjacent genes, some of which are dosage-sensitive
E.g. Williams, DiGeorge
What causes CMT1A and HNPP?
CMT1A - PMP22 dup at 17p11
HNPP - PMP22 del and 17p11
