Updating penetrance estimates for syndromes with variable phenotypic manifestation. Adele Corrigan June 27th

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1 Updating penetrance estimates for syndromes with variable phenotypic manifestation Adele Corrigan June 27th

2 Background Array CGH has led to increased identification of copy number variants (CNVs) Our understanding of the role of CNVs in disease is improving Identified a number of fully penetrant, clinically recognisable syndromes e.g. 15q11.2-q13 deletion Prader-Willi / Angelman syndrome Many others associated with early-onset neurodevelopmental disorders have incomplete penetrance and variable phenotypic manifestation Examples include 1q21.1 del/dup, 16p11.2

3 Challenges Clinician Extended family Genetic counsellor Patient Carrier parent Need for clarity concerning risk

4 Estimating penetrance Few studies have sought to determine penetrance of recurrent CNVs >33,000 postnatal arrays to estimate penetrance of 13 susceptibility regions Rates of these CNVs in patients was compared to those in published control cohorts Penetrance estimates from this study are widely used Replicate this work in a UK based cohort * et al, Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med Jun;15(6):

5 Guy s array cohort Comparable cohort size 31,269 postnatal specimens received for acgh between Penetrance estimates calculated for the same 13 susceptibility regions Samples were tested on Agilent custom design arrays median resolution 125kb Referral indications included developmental delay, intellectual disability, epilepsy, congenital malformations and dysmorphism Same control cohort of 22,246 individuals that were used in the study

6 Penetrance calculation Incidence of CNV in cases Incidence in population Penetrance Incidence of CNV in controls Proportion of population unaffected

7 Incidence Region Copy number Coordinates (hg19) 1q21.1 (RBM8A) Distal 1q21.1 (GJA5) Dup Del Distal 1q21.1 Dup (GJA5) 16p13.11 Del (MYH11) q12 16p12.1 Del (CDR2) Distal 1q Distal 16p11.2 (SH2B1) Distal 16p11.2 (SH2B1) 16p11.2 (TBX6) 16p11.2 (TBX6) Dup q12 Del (HNF1B) q12 Dup (HNF1B) q11.2 Dup (TBX1) Freq. acgh cases 0.17% (85/48,637) 0.29% (97/33,226) 0.28% (93/33,226) 0.09% (29/33,226) 0.11% (37/33,226) 0.28% (136/48,637) Freq. acgh cases Guy s 0.11% (35/31,269) 0.12% (39/31,269) 0.21% (65/31,269) 0.05% (17/31,269) 0.09% (29/31,269) 0.16% (50/31,269) Population Region Copy number Coordinates Freq. Freq. Guy s Region Copy number Coordinates Freq. Freq. Guys 0.20% 0.06% 16p12.1 Deletion % 0.21% (68/33,226) (18/31,269) (CDR2) Distal 1q21.1 Deletion (62/33,226) 0.29% (66/31,269) 0.12% (GJA5) 0.15% 0.07% (97/33,226) (39/31,269) (50/33,226) (21/31,269) Duplication % 0.09% 0.19% 0.21% (HNF1B) Duplication (62/33,226) (66/31,269) (37/33,226) 0.20% (29/31,269) 0.06% (GJA5) Del % % (68/33,226) (18/31,269) Distal 16p Deletion (46/33,226) (31/31,269) % 0.10% (SH2B1) 22q11.2 Dup Duplication 0.11% % (46/33,226) 0.28% (31/31,269) 0.16% (35/33,226) (18/31,269) (TBX1) (136/48,637) (50/31,269) 17q12 Del Deletion 0.44% % Access 0.09% to testing 0.05% (146/33,226) (99/31,269) (HNF1B) 16p13.11 Deletion (29/33,226) 0.15% (17/31,269) 0.07% (MYH11) (50/33,226) (21/31,269) 16p11.2 (TBX6) Deletion % (146/33,226) 0.32% (99/31,269)

8 Region Copy number Coordinates (hg19) Freq. acgh cases Penetrance estimates Freq. acgh cases Guy s Freq. controls P value P value Penetrance estimate estimate estimate (95% CI) Dup % 0.11% (10/22,246) << Put in a table of penetrance estimate results (85/48,637) (35/31,269) 0.04% ( ) 16p12.1 (del) q21.1 (RBM8A) Distal 1q21.1 (GJA5) Del % (97/33,226) 0.12% (39/31,269) (6/22,246) 0.03% << ( ) Prox. Highlight 1q21.1 DupFreq (dup) the Freq Guys 0.20% key Freq. differences 0.06% (6/22,246) P value << between P value Penetrance our (68/33,226) controls (18/31,269) 0.03% Guy s ( ) Del % 0.07% (12/22,246) < q11.2 study 0.29% (dup) and % s (50/33,226) 0.03% (21/31,269) 0.05% << Region Distal 1q21.1 (GJA5) 16p13.11 (MYH11) 16p12.1 (CDR2) Distal 16p11.2 (Del) (SH2B1) Distal 16p11.2 (SH2B1) (Dup) 16p11.2 (TBX6) 16p11.2 (TBX6) 17q12 (HNF1B) 17q12 (HNF1B) 22q11.2 (TBX1) Region Coordinates Penetrance Distal 1q21.1 (Dup) 16p13.11 Distal 16p11.2 (97/33,226) Del Del (50/33,226) Dup Del Dup Del Dup Dup % (62/33,226) 0.14% (46/33,226) 0.11% (35/33,226) 0.44% (146/33,226) 0.28% (93/33,226) 0.09% (29/33,226) 0.11% (37/33,226) 0.28% (136/48,637) 0.21% (66/31,269) 0.10% (31/31,269) 0.06% (18/31,269) 0.32% (99/31,269) 0.21% (65/31,269) 0.05% (17/31,269) 0.09% (29/31,269) 0.16% (50/31,269) (16/22,246) 0.07% (1/22,246) 0.005% (10/22,246) 0.04% (6/22,246) 0.03% (9/22,246) 0.04% (2/22,246) 0.01% (5/22,246) 0.02% (12/22,246) 0.05% ( ) ( ) 17q12 (dup) 0.15% 0.07% % 21.1 Distal 1q % (del) 0.06% % 36.9 (35/33,226) (39/31,269) (21/31,269) (18/31,269) (6/22,246) (12/22,246) (10/22246) Penetrance Guy s ( ) 11.8 ( ) ( ) 13.8 ( ) < < ( ) < << < ( ) ( ) ( ) < < ( ) ( ) Prox. 16p11.2 (dup) << < ( ) ( ) 17q12 (del) << < ( ) ( ) Prox. 16p11.2 (del) < ( ) ( ) Distal 16p11.2 (del) < ( ) << ( ) ( ) Penetrance estimate (95% CI) Guy s 11.8 ( ) 20.0 ( ) 6.3 ( ) 10.3 ( ) ( )( ) ( ) 54.3 ( ) ( )( ) ( ) ( ) ( )( ) 21.7 ( ) 24.6 ( ) 38.8 ( ) 54.3 ( ) Penetrance 10.3 Guy s ( ) ( ) 21.7 ( ) 24.6 ( ) 18.2 ( ) 13.8 ( )

9 Limitations Population prevalence (prior risk) ~5% based on data from a study carried out between Wide range of phenotypes, differing severity considered together Separation may give a more accurate estimation of population incidence Some patients will have multiple CNVs No stratification based on ancestral substructure within the population larger sample size needed Cannot guarantee that control population was unaffected Still a relatively small sample size when considering rare CNV

10 Collaboration Needed Ideally we would collect data from a range of centres to improve the estimates More robust picture of CNV incidence Improve feasibility of stratification

11 Contact: Acknowledgements Mike Coldwell Sarah Chu Joo Wook Ahn Cathryn Lewis Claudio Romero Sue Bint Caroline Ogilvie

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