L'haploinsuffisence pour les gènes ANKRD11 fait la différence entre les syndromes de microdélétion de KBG et 16q24.3: 12 nouveaux cas

Aperçu: G.M.

La suppression 16q24 impliquant le gène ANKRD11, allant de 137 kb à 2 Mb, a été associée à un syndrome de microdélétion caractérisé par une déficience cognitive variable, un trouble du spectre de l'autisme, des dysmorphies faciales avec des anomalies dentaires, des anomalies cérébrales affectant essentiellement le corps calleux et une faible taille.

 

Eur J Hum Genet. 2017 Apr 19. doi: 10.1038/ejhg.2017.49.

Haploinsufficiency for ANKRD11-flanking genes makes the difference between KBG and 16q24.3 microdeletion syndromes: 12 new cases

Novara F¹, Rinaldi B¹, Sisodiya SM^2,3, Coppola A⁴, Giglio S^5,6, Stanzial F⁷, Benedicenti F⁷, Donaldson A⁸, Andrieux J⁹, Stapleton R¹⁰, Weber A¹¹, Reho P¹, van Ravenswaaij-Arts C¹², Kerstjens-Frederikse WS¹², Vermeesch JR¹³, Devriendt K¹³, Bacino CA^14,15, Delahaye A^16,17,18, Maas SM^19,20, Iolascon A^21,22, Zuffardi O¹.

Author information

1

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

2

Department of Clinical and Experimental Epilepsy, NIHR University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK.

3

The Epilepsy Society, Chalfont-St-Peter, Bucks, UK.

4

Epilepsy Centre, Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.

5

Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.

6

Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

7

Servizio di Consulenza Genetica, Centro Provinciale di Coordinamento della Rete delle Malattie Rare, Azienda Sanitaria dell'Alto-Adige, Bolzano, Italy.

8

Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.

9

Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, France.

10

Genetic Health Service NZ-Northern Hub, Building 30 Auckland City Hospital, Auckland, New Zealand.

11

Merseyside and Cheshire Clinical Genetics Service, Liverpool Women's (NHS) Foundation Hospital Trust, Liverpool, UK.

12

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

13

Laboratory of Cytogenetics and Genome Research, Center of Human Genetics, KU Leuven, Leuven, Belgium.

14

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

15

Texas Children's Hospital, Houston, TX, USA.

16

INSERM, UMR 1141, Robert Debré University Hospital, Paris, France.

17

Cytogenetics Unit, AP-HP, Jean Verdier Hospital, Bondy, France.

18

Paris 13 University, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.

19

Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.

20

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

21

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

22

CEINGE Biotecnologie Avanzate Scarl, Naples, Italy.

Abstract

16q24 deletion involving the ANKRD11 gene, ranging from 137 kb to 2 Mb, have been associated with a microdeletion syndrome characterized by variable cognitive impairment, autism spectrum disorder, facial dysmorphisms with dental anomalies, brain abnormalities essentially affecting the corpus callosum and short stature. On the other hand, patients carrying either deletions encompassing solely ANKRD11 or its loss-of-function variants were reported in association with the KBG syndrome, characterized by a very similar phenotype, including mild-to-moderate intellectual disability, short stature and macrodontia of upper incisors, with inter and intrafamilial variability. To assess whether the haploinsufficiency of ANKRD11-flanking genes, such as ZFPM1, CDH15 and ZNF778, contributed to either the severity of the neurological impairment or was associated with other clinical features, we collected 12 new cases with a 16q24.2q24.3 deletion (de novo in 11 cases), ranging from 343 kb to 2.3 Mb. In 11 of them, the deletion involved the ANKRD11 gene, whereas in 1 case only flanking genes upstream to it were deleted. By comparing the clinical and genetic features of our patients with those previously reported, we show that the severity of the neurological phenotype and the frequency of congenital heart defects characterize the deletions that, besides ANKRD11, contain ZFPM1, CDH15 and ZNF778 as well. Moreover, the presence of thrombocytopenia and astigmatism should be taken into account to distinguish between 16q24 microdeletion syndrome and KBG syndrome. The single patient not deleted for ANKRD11, whose phenotype is characterized by milder psychomotor delay, cardiac congenital malformation, thrombocytopenia and astigmatism, confirms all this data.European Journal of Human Genetics advance online publication, 19 April 2017; doi:10.1038/ejhg.2017.49.

PMID: 28422132

DOI: 10.1038/ejhg.2017.49