What to include in an array report?

What to include in an array report? December 17-19, 2007 Nicole de Leeuw, PhD Department of Human Genetics Radboud University Nijmegen Medical Centre The Netherlands

Array analyse criteria a) SNP call >85% (verkregen via het dynamic model algoritme van GTYPE) b) standaard deviatie van de data in CNAG < 0.2050 c) Afwijkingen worden verder geanalyseerd indien: - significant afwijkend met HMM algoritme van CNAG - Deletie: > 150 kb EN 5 SNPs - Gain: > 200 kb EN 7 SNPs d) Een imbalans kan als normale genoomvariant worden geduid indien deze eerder een aantal malen tevens is teruggevonden in niet aangedane controles: i)- In 2 of meer in huis geanalyseerd controles (niet aangedane ouders) ii)- In 3 of meer controles vermeld in (http://projects.tcag.ca/variation/) identieke afwijking (gain of loss); breukpunten ± 100 kb

HMM setting 0,38

PN07-1832

HMM setting 0,35

PN07-1832

Sources for interpretation of array data UCSC Genome Browser: http://genome.ucsc.edu/ Ensembl Genome Browser: http://www.ensembl.org/homo_sapiens/index.html Database of Genomic Variants: http://projects.tcag.ca/variation/ http://www.ecaruca.net http://www.sanger.ac.uk/postgenomics/decipher/ http://www.ncbi.nlm.nih.gov/ Etc.

Array CGH: array report 46,XY. arr cgh 1p34.3p34.2(RP11-345N12 RP11-336K5)x1 dn Type of array platform (average resolution) Name and version of genome browser a 3.7 Mb loss in 1p34.3p34.2 was observed (39.2 42.9 Mb; number of targets and genes)

Array CGH report: abnormal outcome arr cgh 17p13.1(CTD-2306L18->RP11-74C23)x1 (7.7-8.8 Mb) Abnormal female array CGH profile. Based on our copy number detection criteria, array CGH analysis (whole autosomal genome with average resolution of 300 kb; UCSC genome browser May 2004 assembly) revealed an abnormal pattern, with a 1.1 Mb loss in 17p13.1 (7.7-8.8 Mb) (please find the schematic representation enclosed). This could be the cause of the clinical phenotype, but we advise further examination of this region by FISH and / or MLPA in both the patient and her parents. In addition, four known regions of normal genomic variation were detected: a 700 kb loss in 14q11.1 (18.5-19.2 Mb), a 600 kb loss in 15q11.2 (18.8-19.4 Mb), a 100 kb loss in 19p13.2 (8.7-8.8 Mb), and a 200 kb loss in 22q11.1 (14.5-14.7 Mb). CNVs store in database, but don t mention in report

Array CGH analysis for characterisation 46,XY,der(22)(qter q13.31::q12.1 q10::p10 qter)dn. arr cgh 22q11.1q12.1(RP13-1052J9 RP11-322L6)x3, 22q13.31q13.33(RP11-704G20 RP11-40G15)x3 10,4 Mb gain in 22q11.1q12.1 (15.0-25.4 Mb; 100 BACs) en een 3,3 Mb gain in 22q13.31q13.33 (46.1-49.4 Mb; 36 BACs)

Array report: a normal outcome

chr3:48,603-8,994,748 PN07-0249 en 0250; ind. 23

Array report: an abnormal outcome Please see enclosed prints for illustration.

Array analyse criteria DISCLAIMER SNP array analysis was performed using a 250k Affymetrix SNP array with an average genome wide resolution of 200 kb, excluding the Y chromosome (UCSC genome browser, NCBI build 35 (May 2004)). Inherent to the structure of the human genome, this resolution is not achieved for all regions, such as the centromeric regions and heterochromatic regions. Balanced chromosome rearrangements and triploidy cannot be detected with array (CGH) analysis. Low mosaic genomic imbalances present in less than 10-20% of the cells from which the DNA was isolated may remain undetectable. Experimental conditions are described in WVS POS 624, 625 and 626 (versions 1.0). Specific information can be provided upon request.

Array dragerschapsanalyse De bij dochter (d.o.b.; reference) vastgestelde gain in 12q13 werd bij meneer teruggevonden en kan derhalve worden geduid als een erfelijke gain, waarvan de klinische consequentie vooralsnog niet duidelijk is. Opgemerkt dient te worden dat de array data analyse bij meneer uitsluitend beperkt is tot de regio die bij het kind afwijkend is gevonden. Array data analysis of parental samples is restricted to aberrant region(s) detected in the child.

Discussion Use of up to date sources! Version of genome browsers Cautious interpretation of inherited imbalances - Imprinting effect? - Uncovering a recessive mutation? Imbalance in gene-less region (positional effect?) Distance to normal targets at imbalance boundaries Unexpected findings: i.e. deletion includes BRCA1 (Parental array (CGH) : restrict analysis (use same reference)) More information increase our knowledge improve / expand diagnostic testing www.ecaruca.net

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