Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism

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Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism Publisher Pubmed

Ansari M¹ ; Poke G¹ ; Ferry Q^{2, 3} ; Williamson K¹ ; Aldridge R¹ ; Meynert AM¹ ; Bengani H¹ ; Chan CY¹ ; Kayserili H⁴ ; Avci S⁴ ; Hennekam RCM⁵ ; Lampe AK⁶ ; Redeker E⁵ ; Homfray T⁷ Show All Authors

Ansari M¹
Poke G¹
Ferry Q^{2, 3}
Williamson K¹
Aldridge R¹
Meynert AM¹
Bengani H¹
Chan CY¹
Kayserili H⁴
Avci S⁴
Hennekam RCM⁵
Lampe AK⁶
Redeker E⁵
Homfray T⁷
Ross A⁸
Smeland MF⁹
Mansour S⁷
Parker MJ¹⁰
Cook JA¹⁰
Splitt M¹¹
Fisher RB¹¹
Fryer A¹²
Magee AC¹³
Wilkie A¹⁴
Barnicoat A¹⁵
Brady AF¹⁶
Cooper NS¹⁷
Mercer C¹⁸
Deshpande C¹⁹
Bennett CP²⁰
Pilz DT²¹
Ruddy D¹⁹
Cilliers D²²
Johnson DS¹⁰
Josifova D¹⁹
Rosser E¹⁵
Thompson EM^{23, 24}
Wakeling E¹⁶
Kinning E²⁵
Stewart F¹³
Flinter F¹⁹
Girisha KM²⁶
Cox H¹⁷
Firth HV²⁷
Kingston H²⁸
Wee JS²⁹
Hurst JA¹⁵
Claytonsmith J²⁸
Tolmie J²⁵
Vogt J¹⁷
Tattonbrown K⁷
Chandler K²⁸
Prescott K²⁰
Wilson L¹⁵
Behnam M³⁰
Mcentagart M⁷
Davidson R²⁵
Lynch SA³¹
Sisodiya S³²
Mehta SG²⁷
Mckee SA¹³
Mohammed S¹⁹
Holden S²⁷
Park SM²⁷
Holder SE¹⁶
Harrison V¹⁸
Mcconnell V¹³
Lam WK⁶
Green AJ^{31, 33}
Donnai D²⁸
Bitnerglindzicz M^{15, 34}
Donnelly DE¹³
Nellaker C³
Taylor MS¹
Fitzpatrick DR¹

Source: Journal of Medical Genetics Published:2014

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 '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 mutationnegative group supporting the existence of undetected mosaic cases. Conclusions: Future diagnostic testing in 'mutationnegative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

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Style	Citing Format
MLA	Ansari M, et al.. "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, 2014, pp. 659-668.
APA	Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, Chan CY, Kayserili H, Avci S, Hennekam RCM, Lampe AK, Redeker E, Homfray T, Ross A, Smeland MF, Mansour S, Parker MJ, Cook JA, ... 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, 51(10), 659-668.
Chicago	Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, et al.. "Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism." Journal of Medical Genetics 51, no. 10 (2014): 659-668.
Harvard	Ansari M et al. (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), pp. 659-668.
Vancouver	Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, et al.. Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism. Journal of Medical Genetics. 2014;51(10):659-668.
BibTex	@article{ author = {Ansari M and Poke G and Ferry Q and Williamson K and Aldridge R and Meynert AM and Bengani H and Chan CY and Kayserili H and Avci S and Hennekam RCM and Lampe AK and Redeker E and Homfray T and Ross A and Smeland MF and Mansour S and Parker MJ and Cook JA and Splitt M and Fisher RB and Fryer A and Magee AC and Wilkie A and Barnicoat A and Brady AF and Cooper NS and Mercer C and Deshpande C and Bennett CP and Pilz DT and Ruddy D and Cilliers D and Johnson DS and Josifova D and Rosser E and Thompson EM and Wakeling E and Kinning E and Stewart F and Flinter F and Girisha KM and Cox H and Firth HV and Kingston H and Wee JS and Hurst JA and Claytonsmith J and Tolmie J and Vogt J and Tattonbrown K and Chandler K and Prescott K and Wilson L and Behnam M and Mcentagart M and Davidson R and Lynch SA and Sisodiya S and Mehta SG and Mckee SA and Mohammed S and Holden S and Park SM and Holder SE and Harrison V and Mcconnell V and Lam WK and Green AJ and Donnai D and Bitnerglindzicz M and Donnelly DE and Nellaker C and Taylor MS and Fitzpatrick DR}, title = {Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism}, journal = {Journal of Medical Genetics}, volume = {51}, number = {10}, pages = {659-668}, year = {2014} }
RIS	TY - JOUR AU - Ansari M AU - Poke G AU - Ferry Q AU - Williamson K AU - Aldridge R AU - Meynert AM AU - Bengani H AU - Chan CY AU - Kayserili H AU - Avci S AU - Hennekam RCM AU - Lampe AK AU - Redeker E AU - Homfray T AU - Ross A AU - Smeland MF AU - Mansour S AU - Parker MJ AU - Cook JA AU - Splitt M AU - Fisher RB AU - Fryer A AU - Magee AC AU - Wilkie A AU - Barnicoat A AU - Brady AF AU - Cooper NS AU - Mercer C AU - Deshpande C AU - Bennett CP AU - Pilz DT AU - Ruddy D AU - Cilliers D AU - Johnson DS AU - Josifova D AU - Rosser E AU - Thompson EM AU - Wakeling E AU - Kinning E AU - Stewart F AU - Flinter F AU - Girisha KM AU - Cox H AU - Firth HV AU - Kingston H AU - Wee JS AU - Hurst JA AU - Claytonsmith J AU - Tolmie J AU - Vogt J AU - Tattonbrown K AU - Chandler K AU - Prescott K AU - Wilson L AU - Behnam M AU - Mcentagart M AU - Davidson R AU - Lynch SA AU - Sisodiya S AU - Mehta SG AU - Mckee SA AU - Mohammed S AU - Holden S AU - Park SM AU - Holder SE AU - Harrison V AU - Mcconnell V AU - Lam WK AU - Green AJ AU - Donnai D AU - Bitnerglindzicz M AU - Donnelly DE AU - Nellaker C AU - Taylor MS AU - Fitzpatrick DR TI - Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism JO - Journal of Medical Genetics VL - 51 IS - 10 SP - 659 EP - 668 PY - 2014 ER -