Roberto Ciccone, Orsetta Zuffardi
Università di Pavia
XIII Corso di Formazione
Malformazioni Congenite dalla Diagnosi Prenatale alla Terapia Postnatale
Carrara, 24 ottobre 2014
unipv.eu
Legend: Blue bars indicate reported CNVs; Red bars indicate reported
inversion breakpoints; Green bars to the left indicate segmental
duplications.
Structural Variations (SVs)
Copy Number Variants
(CNVs)
Balanced Chromosomal Aberrations
(BCAs)
Circa 68% del genoma coperto da CNVs
> 90% dei trascritti coperti da CNVs
> 90% dei geni OMIM coperti da CNVs
dgv.tcag.ca/dgv/app/home
dgv.tcag.ca/dgv/app/home
Common CNVs (MAF > 1%):
may determine several multifactorial characters,
have numerous alleles, in term of copy number states
are involved in sensory perception, immune response, disease susceptibility and
drug response
Major source of inter-individual genetic variability
Rare CNVs (MAF < 1%):
often causative of pathological phenotypes
have fewer allelic states, usually hemizygous or trisomic
are highly penetrant
Cooper G et al, Nat Genet 2011
• Size
• Genomic content (genes, repetitive/unique sequences, regulatory
elements)
• Comparison of CNV with internal and external databases
• Inheritance/parental origin
Gene content
When considering the potential phenotypic effect of CNVs it is fundamental to
investigate whether the genes in the interval are associated with clinical
disorders. However….
• Genes associated with a clinical phenotype due to haploinsufficiency
may have no phenotype associated with a copy number gain.
• Dosage imbalance does not imply impairment of gene function
• Copy number gains involving only part of a gene may result in gene
disruption or altered coding sequence
• Single-copy deletions of genes associated with recessive disease may
only suggest carrier status for the condition.
• Small CNVs involving only intronic sequence may have no effect on
gene function
Recessive coding mutations in PTF1A cause syndromic
pancreatic agenesis with neurological features and cerebellar
agenesis.
However, some families have isolated pancreatic agenesis….
Whole Genome Sequencing revealed mutations of a cisregulatory elements of PTF1A
16p12.1 recurrent deletion: benign variant or disease causing
mutation??
16p12.1 recurrent deletion: benign variant or disease causing
mutation??
Nat. Genet, 2010
The frequency of the inherited first hit depends on the purifying selection
Milder phenotypes can easily be passed from parent to child
Girirajan and Eichler, 2010
Clinically relevant CNVs can be identified in 17.6%–22.5% of
cases by Chromosomal MicroArray (CMA)
Cryptic SVs (CNVs <100 Kb and small balanced
rearrangements) can cause pathological phenotypes but
cannot be detected by conventional clinical genetic
screening
Whole-genome sequencing using large-insert jumping libraries
allows detection of cryptic and cytogenetically visible SVs
These investigations revealed about 200 SVs per subject,
the vast majority would be cryptic to conventional CMA
Somatic Genomic Alterations
Proteus syndrome
Proteus syndrome is a severe syndrome
characterized by multiple
overgrowths of the skin, bone,
connective tissue, and other tissues
caused by a dominant
somatic mutation of the AKT1 gene.
Some syndromes caused by germline mutations (i.e. NF1, TSC1
and TSC2…..) present characteristics due to additiona somatic
mutations.
Somatic Genomic Alterations
Post-zygotic chromosomal aberrations are very well known cause
of syndromic phenotypes (i.e: terminal del/dup mimicking
unbalanced translocations)
Recently it has been demonstrated that somatic mutations
confined at the CNS may cause cortical malformation and
neurodegenerative diseases
Somatic Activation of AKT3 Causes Hemispheric
Developmental Brain Malformations
Poduri et al, 2012