1.  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.

3.  The population prevalence of learning difficulties and congenital abnormalities is ~3%  First line SNP array testing introduced in 2011 › 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.

4. Case 1:  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

5. 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 AA AB BB AA/AB BB/AB

6. Case 2:  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

7. Case 2:  Paternal follow up: arr 15q26.2(94,768,611- 98,324,871)x1~2 › ~30% mosaicism for the abnormal cell line in father’s blood › Recurrence risk in this family is high

8. Case 3:  Infant, born at 27/40 following a maternal history of pre- eclampsia. 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

9. 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

10.  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.

11. Case 1:  arr 3q26.2(168,327,604- 168,914,340)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

12. Case 2  Decreased platelets and neutrophils, ?MDS  arr 19q13.32(45,410,461-45,948,162)x1 c › 538kb deletion of 19q13.32 › Deletion contains two genes APOE, ERCC1  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

13. 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 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