Genotype differences in cognitive functioning in Noonan syndrome

Abstract

Noonan syndrome (NS) is an autosomal-dominant genetic disorder associated with highly variable features, including heart disease, short stature, minor facial anomalies and learning disabilities. Recent gene discoveries have laid the groundwork for exploring whether variability in the NS phenotype is related to differences at the genetic level. In this study, we examine the influence of both genotype and nongenotypic factors on cognitive functioning. Data are presented from 65 individuals with NS (ages 4-18) who were evaluated using standardized measures of intellectual functioning. The cohort included 33 individuals with PTPN11 mutations, 6 individuals with SOS1 mutations, 1 individual with a BRAF mutation and 25 participants with negative, incomplete or no genetic testing. Results indicate that genotype differences may account for some of the variation in cognitive ability in NS. Whereas cognitive impairments were common among individuals with PTPN11 mutations and those with unknown mutations, all of the individuals with SOS1 mutations exhibited verbal and nonverbal cognitive skills in the average range or higher. Participants with N308D and N308S mutations in PTPN11 also showed no (or mild) cognitive delays. Additional influences such as hearing loss, motor dexterity and parental education levels accounted for significant variability in cognitive outcomes. Severity of cardiac disease was not related to cognitive functioning. Our results suggest that some NS-causing mutations have a more marked impact on cognitive skills than others.

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…Some studies have reported that children with NS have stronger verbal reasoning abilities relative to nonverbal reasoning abilities (Pierpont et al 2009;van der Burgt et al 1999), whereas other studies have found the opposite pattern (D. A. Lee et al 2005) or no significant difference between these domains (Pierpont et al 2015).…”

“…The percentage of individuals with NS scoring in the IQ range associated with intellectual disability (IQ<70) varies from 6 to 23 % across studies (van der Burgt et al 1999;Pierpont et al 2015), representing an increased risk relative to the general population. Despite this increased risk, the majority of people with NS have intellectual functioning within the average range (Pierpont et al 2009;Wingbermühle et al 2012b). It is notable that more recent studies report somewhat higher IQ estimates (Table 3).…”

“…In this study, children with a greater number of physical characteristics (based on a clinical severity rating involving facial features, heart disease, short stature, and chest wall abnormalities) had significantly lower verbal IQ and fluid reasoning as compared to those exhibiting fewer physical criteria. With respect to cardiac risk, Pierpont et al (2009) did not find a significant association between heart disease severity ratings and verbal or nonverbal cognitive abilities in a relatively large sample of children with NS. While congenital heart disease is known to confer risk for neurocognitive deficits, intellectual impairments are most frequently seen for cyanotic conditions or those requiring open heart surgery in the neonatal period (Marino et al 2012), which occur in a relatively small percentage of children with NS (Colquitt and Noonan 2014).…”

“…As more comprehensive genetic testing for NS and other RASopathies has become available, better diagnostic precision among research samples has been possible. Regarding gender comparisons, larger studies have generally failed to find differences in intellectual functioning between boys and girls with NS (e.g., Pierpont et al 2009). …”

“…Regarding sensory functions, one study reported that hearing loss in NS was associated with greater impairments on verbal reasoning tasks (Pierpont et al 2009). Hearing loss is more common in children with NS than in the general population (Qiu et al 1998), and many individuals experience frequent ear infections in childhood ).…”