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Roberto Ciccone, Orsetta Roberto Ciccone, Orsetta Roberto Ciccone, Orsetta Roberto Ciccone, Orsetta ZuffardiZuffardiZuffardiZuffardi

Università di PaviaUniversità di PaviaUniversità di PaviaUniversità di Pavia

XIII Corso di Formazione

Malformazioni Congenite dalla Diagnosi Prenatale alla Terapia Postnatale

Carrara, 24 ottobre 2014

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)

dgv.tcag.ca/dgv/app/home

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

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 cis-

regulatory 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 childGirirajan 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

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

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 HemisphericDevelopmental Brain Malformations

Poduri et al, 2012