Autism, Susceptibility To, X-Linked 4

A number sign (#) is used with this entry because of evidence that X-linked susceptibility to autism-4 (AUTS4) is caused by mutation in the PTCHD1 gene (300828) on chromosome Xp22.

Patients with a similar phenotype have been found to have a contiguous gene deletion on chromosome Xp22 that disrupts the PTCHD1 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, stereotypical, 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).

Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options.

Clinical Features

Marshall et al. (2008) reported a boy with autism who inherited a hemizygous deletion of chromosome Xp22.11 encompassing the PTCHD1 gene from his unaffected mother. His dizygotic twin brother, who had developmental delay, also carried the deletion. The proband was ascertained from a larger group of 427 probands with autism spectrum disorder who were studied for genomewide copy number variation (CNV). Noor et al. (2010) stated that the deletion in this family was 167 kb and included exon 1 of PTCHD1. Analysis of the mother showed highly skewed X inactivation (94:6).

Filges et al. (2011) reported 2 Italian brothers who inherited a 200-kb interstitial deletion of Xp22.11 including the PTCHD1 gene from their unaffected mother. The proband was a 6.5-year-old boy with significantly delayed psychomotor development, hypotonia, autistic features, and no expressive speech. He had limited emotional nonverbal contact, but stereotyped or compulsive behavior was not observed. His 20-year-old brother had mental retardation and hypotonia, but no autistic features. Both patients had a history of transient ataxia in early childhood, and neither had dysmorphic features.

Chaudhry et al. (2015) reported 23 patients from 16 families with intellectual disability and/or features of ASD associated with heterozygous deletions of chromosome Xp22 disrupting the PTCHD1 gene. The cohort included 5 individuals from 3 unrelated families who had point mutations in the PTCHD1 gene resulting in premature termination. Four of the families had previously been reported (Marshall et al., 2008; Filges et al., 2011; Noor et al., 2010; Pinto et al., 2010; Whibley et al., 2010). The only female in the cohort was a 5-year-old girl with speech delay and ASD. Eighteen patients (78%) had global developmental delay in early childhood, and 9 patients (39%) were formally diagnosed with mild to severe intellectual disability. Fifteen patients (65%) had behavioral and/or psychiatric diagnoses including autism; other behavioral issues included vocal and motor tics, anxiety, attention deficit and/or hyperactivity, impulsivity, aggressive behaviors, and sleep disorder. Six patients (26%) had generalized hypotonia, especially of facial muscles, and 8 patients (35%) had mild vision problems. Although some patients had subtle dysmorphic features, there was not a recognizable pattern of congenital anomalies or growth abnormalities. None were reported to have seizures in childhood.

Cytogenetics

In a study of CNV among 996 ASD patients, Pinto et al. (2010) found that 7 patients had maternally inherited deletions at PTCHD1 (300828), implicating this gene in the disorder. When compared with 4,964 controls, the association was significant (p = 3.6 x 10(-6)).

Among 251 families with X-linked intellectual disability (mental retardation) and autism, Whibley et al. (2010) found 1 family in which a 90-kb deletion upstream of the PTCHD1 gene from 23,239,008-23,329,210 segregated in 2 affected brothers and an affected uncle. The deletion was not found in 447 controls.

Noor et al. (2010) reported a boy with intellectual disability and dysmorphic features who had a 146-kb deletion spanning PTCHD1 and upstream regions (23,146,927-23,293,273). Noor et al. (2010) also identified several variants in the PTCHD1 gene that were transmitted from an unaffected mother to a son with X-linked intellectual disability or autism, but functional characterization was not performed and the variants did not fully segregate with the phenotype in all families. Finally, Noor et al. (2010) found 11 deletions mapping upstream of the PTCHD1 gene in patients with autism and/or intellectual disability. Overall, the findings suggested that CNV at Xp22 may confer susceptibility to various disorders of cognitive impairment.

Chaudhry et al. (2015) identified heterozygous deletions that disrupted the PTCHD1 gene in affected individuals from 13 families with a neurodevelopmental disorder and/or AUTSX4. The deletions ranged from 46 to 963 kb, and most were inherited from unaffected mothers. There were no apparent genotype/phenotype correlations and functional studies were not performed.

Molecular Genetics

In 5 male members of 3 unrelated families of European origin with AUTSX4, Chaudhry et al. (2015) identified 3 different truncating mutations in the PTCHD1 gene (300828.0001-300828.0003). Functional studies of the variants and studies of patient cells were not performed.

Animal Model

Wells et al. (2016) found that Ptchd1 in postnatal mice was selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1-null male mice showed increased distractibility, hyperactivity, impaired learning, hypotonia, hyperaggression, and hyperfragmented sleep compared to wildtype. These changes were associated with a significant decrease in repetitive burst firing in the neurons in the TRN, which resulted from a decrease in small conductance calcium-activated potassium (SK) channels. TRN neurons in mutant mice also showed reduced burst firing in sleep and an overall reduction in sleep spindle count, which may have led to sleep instability. Conditional knockdown of the Ptchd1 gene specifically in the TRN resulted in attention deficits and hyperactivity, but did not cause learning impairment, hypotonia, or hyperaggression. Pharmacologic boosting of SK currents mitigated impaired sensory-evoked thalamic inhibition and improved distractibility and hyperactivity in germline knockout mice. The findings suggested that decreased TRN neuronal activity resulted in diminished overall thalamic inhibition, and supported SK channel dysfunction as a cellular mechanism for certain behavioral abnormalities. Wells et al. (2016) suggested that a 'leaky thalamus' caused by impaired TRN function could underlie attention deficits, hyperactivity, and sleep disruption across various neurodevelopmental disorders.