Autism, Susceptibility To, X-Linked 5

A number sign (#) is used with this entry because X-linked autism-5 (AUTSX5) is associated with mutation in the RPL10 gene (312173).

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.

Clinical Features

Klauck et al. (2006) identified 2 families each with 2 autistic sibs carrying mutations in the RPL10 gene (AUTSX5). The first family, labeled 42, comprised dizygotic twin brothers. The pregnancy was complicated by intermittent bleeding between weeks' 14 and 20 of gestation. At 31 weeks' gestation, the twins were delivered by cesarean section. They were evaluated at 8 years of age. Twin 1 had a birth weight of 1400 g, had severe intraventricular hemorrhage in the right parietal lobe, and developed left-sided hemiplegia and seizures. He met full criteria for autism on the Autism Diagnostic Instrument-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) evaluations, and his IQ was between 20 and 34. Cranial computed tomography (CCT) revealed a 'chicken eye big porus' at the frontal lobe region, medium-to-higher grade dilation of the right ventricle, and low-to-medium sized dilation of the left ventricle. The porus was taken as a residuum of the perinatal hemorrhage. The second twin had a birth weight of 970 g. He did not suffer intraventricular hemorrhage but was clearly developmentally delayed at 12 months and developed stereotypic behaviors and repetitive manners. At 7 years of age he was placed in a school for language delayed children due to his autistic behavior of delayed communication and social interaction although he did not show gross language delay. He met the diagnosis of autism according to ADI-R and ADOS criteria with a verbal IQ of 82 and a performance IQ of 80. There was a maternal family history of both schizophrenia and seizures; however, none of these persons could be tested molecularly. The second family reported by Klauck et al. (2006), which was labeled family 277, comprised 2 brothers with autistic disorder, age 5 and 3 years at time of assessment. Both had classic features of autism. The older brother had an IQ estimated between 50 and 69; the younger brother was diagnosed with autism based on the ADOS screen but had not had formal IQ testing nor could the ADI-R be administered due to his age and language delay.

Chiocchetti et al. (2011) identified a patient from a German family carrying an RPL10 mutation. When evaluated at 15 years of age, he had a verbal IQ of 94 and a performance IQ of 98.5. He scored positive for autism using the ADI-R. Neural exam was normal. The pregnancy had been complicated by preeclampsia. Gross motor skills were normal. He said his first words at age 2 years and could say short sentences at 4 years of age. He was not toilet trained until age 7 years.

Molecular Genetics

Klauck et al. (2006) sequenced 4 candidate genes on chromosome Xq28, STK23, HCFC1 (300019), RPL10, and ATP6AP1 (300197), in 27 well-characterized patients with autistic disorder and mental retardation. A mutation in RPL10 was detected in 1 of these patients. Klauck et al. (2006) subsequently screened 345 patients from Germany with autistic disorder representing 296 independent families for mutation in RPL10. They identified 2 missense mutations (L206M, 312173.0001 and H213Q, 312173.0002) in 4 patients from 2 independent families. Both mutations involved conserved residues at the distal end of exon 7, the final coding exon of RPL10. Both were inherited from a neurotypical mother. In functional analysis, Klauck et al. (2006) found that ectopic expression of mutant human RPL10 carrying either of the missense mutations results in distinct ribosomal profiles: a small polysome population, a very large 80S population, and an increase in the free 60S and 40S subunit populations.

Gong et al. (2009) sequenced the RPL10 gene in 141 individuals with autism spectrum disorder and identified no nonsynonymous mutations. Furthermore, Gong et al. (2009) found similar transcript levels of RPL10 in male and female controls and found no significant difference in RPL10 transcript levels between cases and controls. Gong et al. (2009) concluded that RPL10 has no major effect on susceptibility to autism spectrum disorders.

Chiocchetti et al. (2011) performed a replication study in a larger cohort of German patients including 176 new ASD patients collected throughout Germany since 2006. They reported, in their cohort of 416 male and 105 female patients from 467 independent families, that RPL10 did not reach statistical significance as an ASD gene; however, they identified another individual carrying the H213Q mutation. Chiocchetti et al. (2011) found normal RPL10 expression in probands with H213Q mutant alleles, non-RPL10 mutated autism patients, and healthy controls. Chiocchetti et al. (2011) found random X inactivation in the mother of the proband carrying the H213Q mutation identified by Klauck et al. (2006), but not for the mutation carriers of the new family. The mother showed an inactivation of 85% and the sister of 89% of one X chromosome. Comparison of alleles and X chromosome inactivation showed that the mother and sister did not inactivate the same allele. This led to the conclusion that either the RPL10 mutation was not conferring the skewed XCI or that there had been a crossover of the 2 maternal X chromosomes during meiosis.