Are 22q11.2 distal deletions associated with math difficulties?

Abstract

Approximately 6% of school-aged children have math difficulties (MD). A neurogenetic etiology has been suggested due to the presence of MD in some genetic syndromes such as 22q11.2DS. However, the contribution of 22q11.2DS to the MD phenotype has not yet been investigated. This is the first population-based study measuring the frequency of 22q11.2DS among school children with MD. Children (1,564) were identified in the schools through a screening test for language and math. Of these children, 152 (82 with MD and 70 controls) were selected for intelligence, general neuropsychological, and math cognitive assessments and for 22q11.2 microdeletion screening using MLPA. One child in the MD group had a 22q11.2 deletion spanning the LCR22-4 to LCR22-5 interval. This child was an 11-year-old girl with subtle anomalies, normal intelligence, MD attributable to number sense deficit, and difficulties in social interactions. Only 19 patients have been reported with this deletion. Upon reviewing these reports, we were able to characterize a new syndrome, 22q11.2 DS (LCR22-4 to LCR22-5), characterized by prematurity; pre- and postnatal growth restriction; apparent hypotelorism, short/upslanting palpebral fissures; hypoplastic nasal alae; pointed chin and nose; posteriorly rotated ears; congenital heart defects; skeletal abnormalities; developmental delay, particularly compromising the speech; learning disability (including MD, in one child); intellectual disability; and behavioral problems. These results suggest that 22q11.2 DS (LCR22-4 to LCR22-5) may be one of the genetic causes of MD.

Behavioral abnormalities are common and severe in patients with distal 22q11.2 microdeletions and microduplications

“…A phenotype is emerging for deletion of the D–E segment (Carvalho et al. 2014; Mikhail et al. 2014), but other abnormalities are relatively rare and information is lacking.…”

“…Carvalho et al. (2014) have presented a recent literature review of all patients with this deletion with the exception of the six cases reported by Mikhail et al. (2014).…”

“…However, abnormalities in 22q11.2 but distal to the DiGeorge/velocardiofacial region and generated using the 5 distal repeats D-H are increasingly being reported. A phenotype is emerging for deletion of the D-E segment (Carvalho et al 2014;Mikhail et al 2014), but other abnormalities are relatively rare and information is lacking.…”

“…2014; Carvalho et al. 2014). Detailed information regarding the phenotypic range of both deletions and duplications is essential in order to counsel and provide appropriate surveillance and management for patients and their families.…”

“…Microduplications of both proximal and distal portions of the band are more commonly inherited and often milder than the deletions (Coppinger et al 2009;Ou et al 2008;Wincent et al 2010). Consequently, more reports of individuals with deletions have been published (summarized in Fagerberg et al 2013;Mikhail et al 2014;Carvalho et al 2014). Detailed information regarding the phenotypic range of both deletions and duplications is essential in order to counsel and provide appropriate surveillance and management for patients and their families.…”