13q Deletion Syndrome Involving RB1: Characterization of a New Minimal Critical Region for Psychomotor Delay

Abstract

Retinoblastoma (RB) is an ocular tumor of the pediatric age caused by biallelic inactivation of the RB1 gene (13q14). About 10% of cases are due to gross-sized molecular deletions. The deletions can involve the surrounding genes delineating a contiguous gene syndrome characterized by RB, developmental anomalies, and peculiar facial dysmorphisms. Overlapping deletions previously found by traditional and/or molecular cytogenetic analysis allowed to define some critical regions for intellectual disability (ID) and multiple congenital anomalies, with key candidate genes. In the present study, using array-CGH, we characterized seven new patients with interstitial 13q deletion involving RB1. Among these cases, three patients with medium or large 13q deletions did not present psychomotor delay. This allowed defining a minimal critical region for ID that excludes the previously suggested candidate genes (HTR2A, NUFIP1, PCDH8, and PCDH17). The region contains 36 genes including NBEA, which emerged as the candidate gene associated with developmental delay. In addition, MAB21L1, DCLK1, EXOSC8, and SPART haploinsufficiency might contribute to the observed impaired neurodevelopmental phenotype. In conclusion, this study adds important novelties to the 13q deletion syndrome, although further studies are needed to better characterize the contribution of different genes and to understand how the haploinsufficiency of this region can determine ID.

Keywords: 13q deletion syndrome; NBEA; array-CGH; intellectual disability; retinoblastoma.

Figure 1

Minimal critical region for ID and developmental delay. The figure shows the deletions reported in all the patients involved in the study. Orange lines refer to patients not showing ID and developmental delay; green lines refer to patients showing developmental delay and facial dysmorphisms. Overlapping the CNVs found in these last patients allowed defining a new minimal critical region for ID which contains the 36 genes mentioned in the text.