Genotype differences in cognitive functioning in Noonan syndrome.
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.
Pierpont
E I
EI
Department of Psychology, University of Wisconsin-Madison, Madison, WI 53706, USA. eipierpont@wisc.edu
Pierpont
M E
ME
Mendelsohn
N J
NJ
Roberts
A E
AE
Tworog-Dube
E
E
Seidenberg
M S
MS
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004522:Educational Status; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D008297:Male; D019957:Motor Skills Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D009483:Neuropsychological Tests; D009634:Noonan Syndrome / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D020837:SOS1 Protein / Q000235:genetics
D020837:SOS1 Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11