Autism, Susceptibility To, X-Linked 2

A number sign (#) is used with this entry because X-linked autism-2 (AUTSX2) is associated with mutation in the NLGN4 (300427) gene.

Description

Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006).

For a discussion of genetic heterogeneity of autism, see 209850.

Mapping

Thomas et al. (1999) reported 8 females with small deletions including Xp22.3, 3 of whom showed features of autism. The authors provided several hypotheses, including X inactivation, haploinsufficiency, and mosaicism, to explain why only some of the females monosomic for the deletion had autism.

Molecular Genetics

Jamain et al. (2003) reported a Swedish family in which 1 brother had typical autism and another brother had Asperger syndrome (ASPGX2; 300497). Both patients had a frameshift mutation in the NLGN4 gene (300427.0001), located at Xp22.3.

In all affected members of a large French family in which 10 males had nonspecific X-linked mental retardation, 2 had MRX with autism, and 1 had 'pervasive developmental disorder,' Laumonnier et al. (2004) identified a 2-bp deletion in the NLGN4 gene (300427.0002). Healthy males in the family did not have the deletion, and 1 obligate carrier female had mild mental retardation. Laumonnier et al. (2004) noted that mutations in the NLGN4 gene are involved in a wide spectrum of phenotypes.

Lawson-Yuen et al. (2008) identified a hemizygous 757-kb deletion in the NLGN4 gene (300427.0003) in a boy with autism, mental retardation, and a motor tic. The patient's 9-year-old brother, who carried diagnoses of Tourette syndrome (see 309840) and attention deficit- hyperactivity disorder with mild cognitive deficits, also carried the deletion. The mother, who was a carrier, had a learning disability, depression, and anxiety. Lawson-Yuen et al. (2008) concluded that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric disorders.