The phenotype of recurrent 10q22q23 deletions and duplications

Bregje Wm van Bon (1) , Bert Ba de Vries (1) , Jorune Balciuniene (1) , Gary Fruhman (1) , Sandesh Chakravarthy Sreenath Nagamani (1) , Diane L Broome (1) , Elizabeth Cameron (1) , Danielle Martinet (1) , Eliane Roulet (1) , Sébastien Jacquemont (1) , Jacques Beckmann (1) , Mira Irons (1) , Lorraine Potocki (1) , Brendan Lee (1) , Sau Wai Cheung (1) , Ankita Patel (1) , Melissa Bellina (1) , Margherita Silengo (1) , Angelo Selicorni (1) , Annalisa Vetro (1) , Nine Vam Knoers (1) , Nicole de Leeuw (1) , Rolph Pfundt (1) , Barry Wolf (1) , Petr Jira (1) , Swaroop Aradhya (1) , Pawels Stankiewicz (1) , Han G Brunner (1) , Orsetta Zuffardi (1) , Scott Selleck (1) , James R. Lupski (1)

1 Human Genetics

The genomic architecture of the 10q22q23 region is characterized by two low copy repeats (LCR3 and LCR4) and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs 3-4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCRs3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For the cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3-4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs 3-4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects.

Keywords: 10q; NRG3; BMPR1A

Bregje Wm van Bon, Bert Ba de Vries, Jorune Balciuniene, Gary Fruhman, Sandesh Chakravarthy Sreenath Nagamani, et al.. The phenotype of recurrent 10q22q23 deletions and duplications. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2010.211⟩. ⟨hal-00609409⟩