American Journal of Medical Genetics 132A:347–351 (2005) Joubert Syndrome Is Not a Cause of Classical Autism T.N. Takahashi, 1 * J.E. Farmer, 1 K.K. Deidrick, 1 B.S. Hsu, 1 J.H. Miles, 1 and B.L. Maria 2 1 The Children’s Hospital at the University of Missouri-Columbia, Columbia, Missouri 2 Children’s Research Institute at the Medical University of South Carolina, Charleston, South Carolina A previous report noted a 27% prevalence of autism in Joubert syndrome (JS), raising the question of overlapping etiologies. Family studies have shown that autism is characterized by family loading for a number of specific behavioral and psychiatric disorders and that the sib recurrence risk is around 4%. The purpose of this study is to determine whether children with Joubert and their families show behavioral or genetic char- acteristics similar to autism. Thirty-one volunteer Joubert families were identified. Parents com- pleted a semi-structured family history interview and the Autism Behavioral Checklist. Rates of family loading for neuropsychiatric disorders in the JS families were compared to autism family history data and Down syndrome (DS) controls. The JS families had significantly lower rates of autism, alcoholism, cognitive, and language dis- orders than the autism families. Their rate of depression was lower, but not significantly differ- ent from that found in autism families. None of the JS children met the clinical cut-off for autism based on parental symptom report and the sib recurrence risk was 32% for the JS families compared to 4% for the autism and 0% for DS families. These data indicate that JS is a geneti- cally distinct disorder from autism. Different genes with different inheritance patterns that affect neurodevelopment of the cerebellum could explain the clinical similarities previously re- ported in JS and autism. ß 2005 Wiley-Liss, Inc. KEY WORDS: Joubert; autism; recurrence risks INTRODUCTION Joubert syndrome (JS) is a rare neurodevelopmental disorder characterized by hypoplasia of the cerebellar vermis, hypotonia, ocular motor apraxia, and global developmental delays. The reported male to female ratio is about 2:1. Though the inheritance pattern is considered autosomal recessive based on the number of affected siblings and consanguineous parents, the recurrence risk is often less than 25%, suggesting etiologic heterogeneity [Cantani, 1989; Saraiva and Baraitser, 1992]. Autism is a complex neurodevelopmental disorder charac- terized by social and language deficits, and repetitive and stereotypic behaviors. Autism has a 4:1 male to female sex ratio and the average sibling recurrence risk is about 4% [Ritvo et al., 1989; Bolton et al., 1994], leading many to consider idiopathic autism to be a multifactorial disorder. There have been reports of several children with JS being diagnosed with autism [Holroyd et al., 1991; Ozonoff et al., 1999]. Holroyd et al. reported two siblings with JS, one meeting full DSM-III-R autism diagnostic criteria and the other with autistic beha- viors. Ozonoff and colleagues reported a 27% prevalence of autism in 11 children with JS using DSM-IV criteria. Genetic studies have consistently noted family loading for neuropsychiatric disorders including depression, alcoholism, and anxiety disorders in families of children with autism [Piven et al., 1991; Smalley et al., 1995; Bolton et al., 1998; Piven and Palmer, 1999; Miles et al., 2003], but to date there has been no systematic pedigree analysis of families of individuals with JS. Thus, the first purpose of this study was to analyze family histories from a large uniformly diagnosed population of children with JS to determine whether their families had an increased rate of autism, depression, alcoho- lism, and other neurodevelopmental disorders compared to families of children with autism. The second purpose was to examine the behavioral phenotype of the JS children to determine how many might meet criteria for autism. Based on previous research suggesting a relationship between autism and JS, we hypothesized autistic symptoms in JS might be high, though that alone would not confer any information about overlapping genetic etiologies. On the other hand, if JS families had high genetic loading for the neuropsychiatric disorders found in autism families, it would support the hypothesis that JS, or at least a significant fraction of cases, was caused by genes that also caused autism and conferred milder behavioral phenotypes in gene carriers. MATERIALS AND METHODS Participants Participants included children with JS (N ¼ 47) and their parents, who were attending a national conference sponsored by the Joubert Syndrome Foundation and the National Institute of Neurologic Disease and Stroke. Of the 44 families attending the conference, 98% (N ¼ 43) agreed to participate in the research study. Inclusion criteria included chronologic age less than 18 years old and a medical diagnosis of JS. One family declined to participate and three children were ineligible because they were over 18 years old. Children ranged in age from 0.4 to 16.2 years with a mean age of 6.6 years (SD ¼ 5.3 years) (Table I). The male to female sex ratio was 1.6:1 (29:19). With the exception of one African- American child, participants were Caucasian. Mean age of mothers was 36.7 years (SD ¼ 5.1 years; n ¼ 32) and for fathers was 39.8 years (SD ¼ 5.5 years; n ¼ 31). With the exception of one father, information was available regarding the educa- tional level of these parents. More than half of mothers (63%) and fathers (57%) had achieved a bachelor’s or graduate degree. Of the remaining parents, most were high school Grant sponsor: Missouri Department of Mental Health; Grant sponsor: Division of Mental Retardation and Developmental Disabilities; Grant sponsor: Leda J. Sears Trust. *Correspondence to: T.N. Takahashi, Division of Medical Genetics, The Children’s Hospital, University of Missouri-Colum- bia, #1 Hospital Drive, Columbia, MO 65212. E-mail: takahashin@missouri.edu Received 18 August 2004; Accepted 11 October 2004 DOI 10.1002/ajmg.a.30500 ß 2005 Wiley-Liss, Inc.