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The prognostic and diagnostic value of
DNA analysis using microarrays
I Simonic
Genetics Laboratory, Cambridge University Hospitals NHS
Foundation Trust, Cambridge, UK
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Disclaimer:
The statements in this presentation are
those of the author and not of Affymetrix.
CytoScan has not been cleared or
evaluated by the US FDA.
Clinical Utility of SNP arrays in paediatrics
The population prevalence of learning difficulties
and congenital abnormalities is ~3%
 First line SNP array testing introduced in 2011
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› Overall increase in diagnostic abnormality detection
rates from ~5% to ~15% compared to previous
testing strategies
 Majority of the identified clinically relevant abnormalities
are DNA deletions
 Added value of SNP arrays includes identification of
extended LOH regions (in ~2% of the cases) mainly due
to parental consanguinity or UPD as well as cryptic
mosaicism
Disclaimer:

The statements in this presentation are those of the author and not of Affymetrix.

CytoScan has not been cleared or evaluated by the US FDA.
Case 1:
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Infant with clinical feature of Beckwith-Wiedemann
syndrome incl. macroglossia and increased birth weight.
› Routine array analysis was performed in the first instance
 arr 15q13.2q13.3(31,110,238-32,462,384)x1pat
 Phenotype associated with this deletion is variable and may
include epilepsy
 This result cannot rule out a diagnosis of BWS
 Father has a 50% chance of transmitting the deletion to
any of his future offspring
Case 1:
 Furthermore a mosaic cnLOH at 11p15.5 was identified
 MS-MLPA analysis was performed and the result was
confirmed as paternal segmental UPD for chromosome 11p
 This finding is consistent with the diagnosis of a sporadic
BWS
 The recurrence risk for BWS in this family is very low
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Case 2:
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Female patient with developmental delay, complex
congenital heart disease and skeletal abnormalities
› arr 15q26.2(94,768,611-98,324,871)x1
› 3.6 Mb deletion including 4 ref-seq genes, incl. NR2F2 gene
(MIM*107773) which has been associated with abnormal
angiogenesis and heart formation
Case 2:
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Paternal follow up: arr 15q26.2(94,768,61198,324,871)x1~2
› ~30% mosaicism for the abnormal cell line in father’s blood
› Recurrence risk in this family is high
Case 3:
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Infant, born at 27/40 following a maternal history of preeclampsia. IUGR was noted as well as CHD and multiple
dysmorphic features.
› Array identified 3 large areas of cnLOH on chromosome 16
consistent with UPD16 most likely due to trisomy rescue
› CPM for T16 and associated IUGR are likely
› Similar clinical features in cases with maternal UPD16 were
reported previously
› Recurrence risk in this family is low and would largely depend
on maternal age
Case 4:
 Female patient with a complex phenotype and features of
alpha mannosidosis and glutaric aciduria type I.
› arr 19p13.3p13.11(260,000-19,780,000)x2 hmz
› MAN2B1 (MIM*609458), GCDH (MIM*608801) genes map to
19p13.2
› This could explain this patient’s main clinical problems
› Confirmation by sequencing is required
› Recurrence risk in this family is high
Clinical Utility of SNP arrays in the diagnosis
of myelodysplastic syndromes (MDS)
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MDS constitute a heterogeneous group of
clonal hematopoietic disorders.
Cytogenetic analysis has been the gold
standard for genetic testing in MDS using
methods such as G-banded chromosome
analysis and FISH
› The abnormality rate for clonal cytogenetic
abnormalities is ~50% and many of these confer
prognostic significance such as leukemia-free
survival
Disclaimer:

The statements in this presentation are those of the author and not of Affymetrix.

CytoScan has not been cleared or evaluated by the US FDA.
Case 1:
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arr 3q26.2(168,327,604168,914,340)x4,4q13.3qter(75,490,485-190,948,412)x2
hmz
› LOH containing 4q24 may result in homozygous TET2
mutations associated with MDS/MPD. TET2 mutations are
associated with a favourable prognosis
› Rearrangements of MECOM, in this case an amplification, have
been reported in MDS and are associated with poor prognosis
Case 2
Decreased platelets and neutrophils, ?MDS
 arr 19q13.32(45,410,461-45,948,162)x1 c
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› 538kb deletion of 19q13.32
› Deletion contains two genes APOE, ERCC1
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Mutations in APOE have been associated with many
diseases including sea-blue histiocytosis (MIM#269600)
› This disorder is characterized by splenomegaly and mild
thrombocytopenia (relative decrease of platelets in blood)
 This finding may explain the reason for referral and may be
confirmed by microscopic analysis of bone marrow
 The finding is associated with good prognosis
Conclusions
In the paediatric diagnostics:
SNP arrays enable a 3-fold increase in the diagnostic rate
 10% of clinically relevant abnormalities are of prognostic value,
particularly when identified in a newborn stage
 Majority of reported abnormalities have an impact on family
planning and management of subsequent pregnancies
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In the diagnostics of haematological malignancies
SNP arrays have contributed to an increased understanding of
MDS genetics
 Results of over 25 published studies support the use of arrays
in MDS testing due to better disease classification, identification
of cryptic changes, and prognostication in this heterogeneous
group of disorders
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Acknowledgements:
Amanda Clarkson, Richard Nash, Leeanne Sparnon, Joanne Staines, Carolyn Dunn,
Paul Jenks, Georgina Corfield, Lesley Baker, Natalie Holder, Kim Whinney, Heather
Kitson, Stephen Abbs and our Clinical team