Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Morad Ansari; Gemma Poke; Quentin Ferry; Kathleen Williamson; Roland Aldridge; Alison M Meynert; Hemant Bengani; Cheng Yee Chan; Hülya Kayserili; Şahin Avci; Raoul C M Hennekam; Anne K Lampe; Egbert Redeker; Tessa Homfray; Alison Ross; Marie Falkenberg Smeland; Sahar Mansour; Michael J Parker; Jacqueline A Cook; Miranda Splitt; Richard B Fisher; Alan Fryer; Alex C Magee; Andrew Wilkie; Angela Barnicoat; Angela F Brady; Nicola S Cooper; Catherine Mercer; Charu Deshpande; Christopher P Bennett; Daniela T Pilz; Deborah Ruddy; Deirdre Cilliers; Diana S Johnson; Dragana Josifova; Elisabeth Rosser; Elizabeth M Thompson; Emma Wakeling; Esther Kinning; Fiona Stewart; Frances Flinter; Katta M Girisha; Helen Cox; Helen V Firth; Helen Kingston; Jamie S Wee; Jane A Hurst; Jill Clayton-Smith; John Tolmie; Julie Vogt; Katrina Tatton-Brown; Kate Chandler; Katrina Prescott; Louise Wilson; Mahdiyeh Behnam; Meriel McEntagart; Rosemarie Davidson; Sally-Ann Lynch; Sanjay Sisodiya; Sarju G Mehta; Shane A McKee; Shehla Mohammed; Simon Holden; Soo-Mi Park; Susan E Holder; Victoria Harrison; Vivienne McConnell; Wayne K Lam; Andrew J Green; Dian Donnai; Maria Bitner-Glindzicz; Deirdre E Donnelly; Christoffer Nellåker; Martin S Taylor; David R FitzPatrick

doi:10.1136/jmedgenet-2014-102573

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Morad Ansari, Gemma Poke, Quentin Ferry, Kathleen Williamson, Roland Aldridge, Alison M Meynert, Hemant Bengani, Cheng Yee Chan, Hülya Kayserili, Şahin Avci, Raoul C M Hennekam, Anne K Lampe, Egbert Redeker, Tessa Homfray, Alison Ross, Marie Falkenberg Smeland, Sahar Mansour, Michael J Parker, Jacqueline A Cook, Miranda SplittRichard B Fisher, Alan Fryer, Alex C Magee, Andrew Wilkie, Angela Barnicoat, Angela F Brady, Nicola S Cooper, Catherine Mercer, Charu Deshpande, Christopher P Bennett, Daniela T Pilz, Deborah Ruddy, Deirdre Cilliers, Diana S Johnson, Dragana Josifova, Elisabeth Rosser, Elizabeth M Thompson, Emma Wakeling, Esther Kinning, Fiona Stewart, Frances Flinter, Katta M Girisha, Helen Cox, Helen V Firth, Helen Kingston, Jamie S Wee, Jane A Hurst, Jill Clayton-Smith, John Tolmie, Julie Vogt, Katrina Tatton-Brown, Kate Chandler, Katrina Prescott, Louise Wilson, Mahdiyeh Behnam, Meriel McEntagart, Rosemarie Davidson, Sally-Ann Lynch, Sanjay Sisodiya, Sarju G Mehta, Shane A McKee, Shehla Mohammed, Simon Holden, Soo-Mi Park, Susan E Holder, Victoria Harrison, Vivienne McConnell, Wayne K Lam, Andrew J Green, Dian Donnai, Maria Bitner-Glindzicz, Deirdre E Donnelly, Christoffer Nellåker, Martin S Taylor, David R FitzPatrick

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.

RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.

CONCLUSIONS: Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

Original language	English
Pages (from-to)	659-668
Journal	Journal of Medical Genetics
Volume	51
Issue number	10
Early online date	14 Aug 2014
DOIs	https://doi.org/10.1136/jmedgenet-2014-102573
Publication status	Published - Oct 2014

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Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism
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Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, Ş., Hennekam, R. C. M., Lampe, A. K., Redeker, E., Homfray, T., Ross, A., Falkenberg Smeland, M., Mansour, S., Parker, M. J., Cook, J. A., ... FitzPatrick, D. R. (2014). Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. Journal of Medical Genetics, 51(10), 659-668. https://doi.org/10.1136/jmedgenet-2014-102573

@article{f7e8de15d3ff4b4e9937598ced271f3f,

title = "Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism",

abstract = "BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as {\textquoteleft}NIPBL-like{\textquoteright}. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.CONCLUSIONS: Future diagnostic testing in {\textquoteleft}mutation-negative{\textquoteright} CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.",

author = "Morad Ansari and Gemma Poke and Quentin Ferry and Kathleen Williamson and Roland Aldridge and Meynert, {Alison M} and Hemant Bengani and Chan, {Cheng Yee} and H{\"u}lya Kayserili and {\c S}ahin Avci and Hennekam, {Raoul C M} and Lampe, {Anne K} and Egbert Redeker and Tessa Homfray and Alison Ross and {Falkenberg Smeland}, Marie and Sahar Mansour and Parker, {Michael J} and Cook, {Jacqueline A} and Miranda Splitt and Fisher, {Richard B} and Alan Fryer and Magee, {Alex C} and Andrew Wilkie and Angela Barnicoat and Brady, {Angela F} and Cooper, {Nicola S} and Catherine Mercer and Charu Deshpande and Bennett, {Christopher P} and Pilz, {Daniela T} and Deborah Ruddy and Deirdre Cilliers and Johnson, {Diana S} and Dragana Josifova and Elisabeth Rosser and Thompson, {Elizabeth M} and Emma Wakeling and Esther Kinning and Fiona Stewart and Frances Flinter and Girisha, {Katta M} and Helen Cox and Firth, {Helen V} and Helen Kingston and Wee, {Jamie S} and Hurst, {Jane A} and Jill Clayton-Smith and John Tolmie and Julie Vogt and Katrina Tatton-Brown and Kate Chandler and Katrina Prescott and Louise Wilson and Mahdiyeh Behnam and Meriel McEntagart and Rosemarie Davidson and Sally-Ann Lynch and Sanjay Sisodiya and Mehta, {Sarju G} and McKee, {Shane A} and Shehla Mohammed and Simon Holden and Soo-Mi Park and Holder, {Susan E} and Victoria Harrison and Vivienne McConnell and Lam, {Wayne K} and Green, {Andrew J} and Dian Donnai and Maria Bitner-Glindzicz and Donnelly, {Deirdre E} and Christoffer Nell{\aa}ker and Taylor, {Martin S} and FitzPatrick, {David R}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2014",

month = oct,

doi = "10.1136/jmedgenet-2014-102573",

language = "English",

volume = "51",

pages = "659--668",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BRITISH MED JOURNAL PUBL GROUP",

number = "10",

}

Ansari, M, Poke, G, Ferry, Q, Williamson, K, Aldridge, R, Meynert, AM, Bengani, H, Chan, CY, Kayserili, H, Avci, Ş, Hennekam, RCM, Lampe, AK, Redeker, E, Homfray, T, Ross, A, Falkenberg Smeland, M, Mansour, S, Parker, MJ, Cook, JA, Splitt, M, Fisher, RB, Fryer, A, Magee, AC, Wilkie, A, Barnicoat, A, Brady, AF, Cooper, NS, Mercer, C, Deshpande, C, Bennett, CP, Pilz, DT, Ruddy, D, Cilliers, D, Johnson, DS, Josifova, D, Rosser, E, Thompson, EM, Wakeling, E, Kinning, E, Stewart, F, Flinter, F, Girisha, KM, Cox, H, Firth, HV, Kingston, H, Wee, JS, Hurst, JA, Clayton-Smith, J, Tolmie, J, Vogt, J, Tatton-Brown, K, Chandler, K, Prescott, K, Wilson, L, Behnam, M, McEntagart, M, Davidson, R, Lynch, S-A, Sisodiya, S, Mehta, SG, McKee, SA, Mohammed, S, Holden, S, Park, S-M, Holder, SE, Harrison, V, McConnell, V, Lam, WK, Green, AJ, Donnai, D, Bitner-Glindzicz, M, Donnelly, DE, Nellåker, C, Taylor, MS & FitzPatrick, DR 2014, 'Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism', Journal of Medical Genetics, vol. 51, no. 10, pp. 659-668. https://doi.org/10.1136/jmedgenet-2014-102573

TY - JOUR

T1 - Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

AU - Ansari, Morad

AU - Poke, Gemma

AU - Ferry, Quentin

AU - Williamson, Kathleen

AU - Aldridge, Roland

AU - Meynert, Alison M

AU - Bengani, Hemant

AU - Chan, Cheng Yee

AU - Kayserili, Hülya

AU - Avci, Şahin

AU - Hennekam, Raoul C M

AU - Lampe, Anne K

AU - Redeker, Egbert

AU - Homfray, Tessa

AU - Ross, Alison

AU - Falkenberg Smeland, Marie

AU - Mansour, Sahar

AU - Parker, Michael J

AU - Cook, Jacqueline A

AU - Splitt, Miranda

AU - Fisher, Richard B

AU - Fryer, Alan

AU - Magee, Alex C

AU - Wilkie, Andrew

AU - Barnicoat, Angela

AU - Brady, Angela F

AU - Cooper, Nicola S

AU - Mercer, Catherine

AU - Deshpande, Charu

AU - Bennett, Christopher P

AU - Pilz, Daniela T

AU - Ruddy, Deborah

AU - Cilliers, Deirdre

AU - Johnson, Diana S

AU - Josifova, Dragana

AU - Rosser, Elisabeth

AU - Thompson, Elizabeth M

AU - Wakeling, Emma

AU - Kinning, Esther

AU - Stewart, Fiona

AU - Flinter, Frances

AU - Girisha, Katta M

AU - Cox, Helen

AU - Firth, Helen V

AU - Kingston, Helen

AU - Wee, Jamie S

AU - Hurst, Jane A

AU - Clayton-Smith, Jill

AU - Tolmie, John

AU - Vogt, Julie

AU - Tatton-Brown, Katrina

AU - Chandler, Kate

AU - Prescott, Katrina

AU - Wilson, Louise

AU - Behnam, Mahdiyeh

AU - McEntagart, Meriel

AU - Davidson, Rosemarie

AU - Lynch, Sally-Ann

AU - Sisodiya, Sanjay

AU - Mehta, Sarju G

AU - McKee, Shane A

AU - Mohammed, Shehla

AU - Holden, Simon

AU - Park, Soo-Mi

AU - Holder, Susan E

AU - Harrison, Victoria

AU - McConnell, Vivienne

AU - Lam, Wayne K

AU - Green, Andrew J

AU - Donnai, Dian

AU - Bitner-Glindzicz, Maria

AU - Donnelly, Deirdre E

AU - Nellåker, Christoffer

AU - Taylor, Martin S

AU - FitzPatrick, David R

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2014/10

Y1 - 2014/10

N2 - BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.CONCLUSIONS: Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

AB - BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.CONCLUSIONS: Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

U2 - 10.1136/jmedgenet-2014-102573

DO - 10.1136/jmedgenet-2014-102573

M3 - Article

C2 - 25125236

SN - 0022-2593

VL - 51

SP - 659

EP - 668

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 10

ER -

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

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