Delineation of 15q13.3 microdeletions.
Alice Masurel-Paulet
(1, 2)
,
Joris Andrieux
(3)
,
Patrick Callier
(4)
,
Jean-Marie Cuisset
(5)
,
Cédric Le Caignec
(6)
,
Muriel Holder-Espinasse
(7)
,
Christel Thauvin-Robinet
(1, 2)
,
Bérénice Doray
(8)
,
Elizabeth Flori
(9)
,
Marie-Pierre Alex-Cordier
(10)
,
Mylène Beri
(11)
,
Odile Boute
(7)
,
Bruno Delobel
(12)
,
Anne Dieux
(7)
,
Louis Vallée
(5)
,
Sylvie Jaillard
(13)
,
Sylvie Odent
(14)
,
Bertrand Isidor
(6)
,
Claire Beneteau
(15)
,
Jaqueline Vigneron
(15)
,
Frédéric Bilan
(16)
,
Brigitte Gilbert-Dussardier
(16)
,
Christele Dubourg
(17)
,
Audrey Labalme
(18)
,
C. Bidon
(19)
,
Agnès Gautier
(20)
,
Philippe Pernes
(21)
,
Jean-Michel Pinoit
(22)
,
Frédéric Huet
(1)
,
Francine Mugneret
(1)
,
Bernard Aral
(15)
,
Philippe Jonveaux
(23)
,
Damien Sanlaville
(18)
,
Laurence Faivre
(1, 2)
1
Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
2 Department of Experimental Cardiology
3 Laboratoire de Génétique Clinique
4 Laboratoire de cytogénétique (CHU de Dijon)
5 Service de Neuropédiatrie
6 Service d'ORL et de Chirurgie Cervicofaciale
7 Service de Génétique clinique
8 Service de génétique médicale
9 Laboratoire de Cytogénétique
10 Service de Génétique
11 Service de Génétique [CHRU Nancy]
12 Centre de Génétique Chromosomique
13 Service de Cytogénétique et de Biologie Cellulaire
14 Service de génétique clinique [Rennes]
15 Service de Néonatologie-Génétique
16 Service de Génétique
17 Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes]
18 Service de cytogénétique constitutionnelle
19 Plateau technique de Biologie [CHU de Dijon]
20 Service de Neuropédiatrie
21 Centre de soins Saint Exupery
22 CRAB - Centre Ressources Autisme de Bourgogne (CHU de Dijon)
23 Service de Cytogénétique
2 Department of Experimental Cardiology
3 Laboratoire de Génétique Clinique
4 Laboratoire de cytogénétique (CHU de Dijon)
5 Service de Neuropédiatrie
6 Service d'ORL et de Chirurgie Cervicofaciale
7 Service de Génétique clinique
8 Service de génétique médicale
9 Laboratoire de Cytogénétique
10 Service de Génétique
11 Service de Génétique [CHRU Nancy]
12 Centre de Génétique Chromosomique
13 Service de Cytogénétique et de Biologie Cellulaire
14 Service de génétique clinique [Rennes]
15 Service de Néonatologie-Génétique
16 Service de Génétique
17 Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes]
18 Service de cytogénétique constitutionnelle
19 Plateau technique de Biologie [CHU de Dijon]
20 Service de Neuropédiatrie
21 Centre de soins Saint Exupery
22 CRAB - Centre Ressources Autisme de Bourgogne (CHU de Dijon)
23 Service de Cytogénétique
Patrick Callier
- Function : Author
- PersonId : 762378
- ORCID : 0000-0002-9794-1848
Sylvie Jaillard
- Function : Author
- PersonId : 854067
Damien Sanlaville
- Function : Author
- PersonId : 760022
- ORCID : 0000-0001-9939-2849
- IdRef : 059247878
Abstract
The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical approximately 1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.