Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway.
To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD).



Fifty children were recruited over 10 months through the regional genetics service and advertisements. A range of parent, child, and observational measures were administered including Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale.



Using the Collaborative Programme for Excellence in Autism criteria, 12 out of 40 children with Noonan syndrome (30%) showed ASD, and 12 out of 40 (30%) with partial ASD features and 16 out of 40 (40%) showed non-ASD. The Noonan syndrome ASD group showed male dominance in a ratio of 5:1. In the CFC group, eight out of nine children met the criteria for ASD, with equal sex distribution. Additionally 19 out of 40 (48%) of the Noonan syndrome group and eight out of nine (88.9%) of the CFC group scored met clinical criteria for ADHD. Only one child was in the Costello syndrome group.



This is the first systematic study to suggest a high prevalence of ASD in Noonan and CFC syndromes, and thus offers crucial evidence to support the importance of the Ras/MAPK pathway in the aetiology of ASD. Limitations include the inevitable possibility of a sampling bias in a rare disorder study of this kind.
Division of Neuroscience & Experimental Psychology, Faculty of Biological, Medical & Health Sciences, University of Manchester and Royal Manchester Children's Hospital and Manchester Academic Health Sciences Centre, Manchester, UK.
Shruti
0000-0002-4472-4583
S
Garg
Division of Neuroscience & Experimental Psychology, Faculty of Biological, Medical & Health Sciences, University of Manchester and Royal Manchester Children's Hospital and Manchester Academic Health Sciences Centre, Manchester, UK.
Ami
A
Brooks
Division of Neuroscience & Experimental Psychology, Faculty of Biological, Medical & Health Sciences, University of Manchester and Royal Manchester Children's Hospital and Manchester Academic Health Sciences Centre, Manchester, UK.
Amy
A
Burns
Manchester Centre for Genomic Medicine, Faculty of Biological, Medical & Health Sciences, University of Manchester and Central Manchester Foundation NHS Trust, Manchester, UK.
Emma
E
Burkitt-Wright
Manchester Centre for Genomic Medicine, Faculty of Biological, Medical & Health Sciences, University of Manchester and Central Manchester Foundation NHS Trust, Manchester, UK.
Bronwyn
B
Kerr
Manchester Centre for Genomic Medicine, Faculty of Biological, Medical & Health Sciences, University of Manchester and Central Manchester Foundation NHS Trust, Manchester, UK.
Susan
S
Huson
Centre for Biostatistics, School of Health Sciences, Faculty of Biological, Medical & Health Sciences, University of Manchester, Manchester, UK.
Richard
R
Emsley
Division of Neuroscience & Experimental Psychology, Faculty of Biological, Medical & Health Sciences, University of Manchester and Royal Manchester Children's Hospital and Manchester Academic Health Sciences Centre, Manchester, UK.
Jonathan
J
Green
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology*; D000067877:Autism Spectrum Disorder / Q000150:complications / Q000453:epidemiology*; D002648:Child; D015897:Comorbidity; D004476:Ectodermal Dysplasia / Q000150:complications / Q000235:genetics; D056344:Executive Function / Q000502:physiology; D019066:Facies; D005183:Failure to Thrive / Q000150:complications / Q000235:genetics; D005260:Female; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D009634:Noonan Syndrome / Q000453:epidemiology* / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013706:Temporomandibular Joint Dysfunction Syndrome / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins