Childhood-onset Schizophrenia Probands Research Articles

De novo variants in sporadic cases of childhood onset schizophrenia.

Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.

Common polygenic variation and risk for childhood-onset schizophrenia

Childhood-onset schizophrenia (COS) is a rare and severe form of the disorder, with more striking abnormalities with respect to prepsychotic developmental disorders and abnormities in the brain development compared with later-onset schizophrenia. We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (>100 kb) (Ahn et al. 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia. We examined the association between a direct measure of genetic risk of schizophrenia in 130 COS probands and 103 healthy siblings. Using data from the schizophrenia and autism GWAS of the Psychiatric Genomic Consortia, we selected three risk-related sets of single nucleotide polymorphisms from which we conducted polygenic risk score comparisons for COS probands and their healthy siblings. COS probands had higher genetic risk scores of both schizophrenia and autism than their siblings (P<0.05). Given the small sample size, these findings suggest that COS patients have more salient genetic risk than do AOS.

High rate of disease-related copy number variations in childhood onset schizophrenia

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

Deficits in probabilistic classification learning and liability for schizophrenia

Patients with schizophrenia show deficits in skill learning. We tested the hypothesis that impaired skill learning is associated with liability for schizophrenia by determining if it is present in non-affected siblings of patients. This study examined cognitive skill learning in adolescent siblings of patients with childhood onset schizophrenia (COS), who are at high genetic risk for the disorder, and age-matched controls. A probabilistic classification task was used to assess cognitive skill learning, which has been shown to be impaired in patients with striatal dysfunction or schizophrenia. Differences between the groups emerged within the first 50 trials of training: the controls showed significant learning while the COS siblings did not. Furthermore, after extended training over 800 additional trials the siblings of COS probands reached a lower level of asymptotic performance than controls. These results suggest that a behavioral impairment in probabilistic classification learning in healthy, unaffected siblings mirrors the deficits seen in patients and thus may reflect genetic liability for the disease

Normalization of Cortical Gray Matter Deficits in Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia

Cortical gray matter (GM) abnormalities in patients with childhood-onset schizophrenia (COS) progress during adolescence ultimately localizing to prefrontal and temporal cortices by early adult age. A previous study of 52 nonpsychotic siblings of COS probands had significant prefrontal and temporal GM deficits that appeared to "normalize" by age 17 years. Here we present a replication with nonoverlapping groups of healthy full siblings and healthy controls. Using an automated measure and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in nonpsychotic full siblings (n = 43, 68 scans; ages 5 through 26 years) of patients with COS, contrasting them with age-, gender-, and scan interval-matched healthy controls (n = 86, 136 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. As in our previous study, young nonpsychotic siblings (<17 years) showed significant GM deficits in bilateral prefrontal and left temporal cortices and, in addition, smaller deficits in the parietal and right inferior temporal cortices. These deficits in nonpsychotic siblings normalized with age with minimal abnormalities remaining by age 17. Our results support previous findings showing nonpsychotic siblings of COS probands to have early GM deficits that ameliorate with time. At early ages, prefrontal and/or temporal loss may serve as a familial/trait marker for COS. Late adolescence appears to be a critical period for greatest localization of deficits in probands or normalization in nonpsychotic siblings.

Hippocampal Volume Development in Healthy Siblings of Childhood-Onset Schizophrenia Patients

Previous anatomic studies have established a reduction in hippocampal volume in schizophrenia, but few have investigated the progressive course of these changes and whether they are trait markers. In the present study, the authors examined hippocampal volumes in relation to age for patients with childhood-onset schizophrenia, their nonpsychotic healthy siblings, and healthy comparison subjects. Anatomic brain magnetic resonance scans were obtained in childhood-onset schizophrenia probands (N=89, 198 scans), their nonpsychotic full siblings (N=78, 172 scans), and matched healthy comparison subjects (N=79, 198 scans) between the ages of 10 and 29 years. Total, left, and right hippocampal volumes were measured using FreeSurfer software and analyzed using a linear mixed-model regression covarying for sex and intracranial volume. Childhood-onset schizophrenia probands had a fixed reduction in hippocampal volumes (total, left, and right) relative to both nonpsychotic siblings and healthy comparison subjects, whereas there were no significant volumetric or trajectory differences between nonpsychotic siblings and healthy comparison subjects. Fixed hippocampal volume loss seen in childhood-onset schizophrenia, which is not shared by healthy siblings, appears to be related to the illness. Decreased hippocampal volume is not strongly genetically related but represents an important intermediate disease phenotype.

Sex chromosome anomalies in childhood onset schizophrenia: an update

Sex chromosome anomalies in childhood onset schizophrenia: an update

Cortical Brain Development in Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia

Cortical gray matter (GM) loss is marked and progressive in childhood-onset schizophrenia (COS) during adolescence but becomes more circumscribed by early adulthood. Nonpsychotic siblings of COS probands could help evaluate whether the cortical GM abnormalities are familial/trait markers. To map cortical development in nonpsychotic siblings of COS probands. Using an automated measurement and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in healthy full siblings (n = 52, 113 scans; age 8 through 28 years) of patients with COS, contrasting them with age-, sex-, and scan interval-matched healthy controls (n = 52, 108 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. An ongoing COS study at the National Institute of Mental Health. Fifty-two healthy full siblings of patients with COS, aged 8 through 28 years, and 52 healthy controls. Longitudinal trajectories of cortical GM development in healthy siblings of patients with COS compared with matched healthy controls and exploratory measure of the relationship between developmental GM trajectories and the overall functioning as defined by the Global Assessment Scale (GAS) score. Younger, healthy siblings of patients with COS showed significant GM deficits in the left prefrontal and bilateral temporal cortices and smaller deficits in the right prefrontal and inferior parietal cortices compared with the controls. These cortical deficits in siblings disappeared by age 20 years and the process of deficit reduction correlated with overall functioning (GAS scores) at the last scan. Prefrontal and temporal GM loss in COS appears to be a familial/trait marker. Amelioration of regional GM deficits in healthy siblings was associated with higher global functioning (GAS scores), suggesting a relationship between brain plasticity and functional outcome for these nonpsychotic, nonspectrum siblings.

Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness?

Background Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. Methods Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). Results Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Asperger's disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD ( n = 12) than for the non-PDD ( n = 27) subgroup (−19.5 ± 11.3 mL/year vs. −9.6 ± 15.3 mL/year; p = .05). None of eight candidate genes for autism were associated with COS or COS-PDD. Conclusions Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.

Childhood onset schizophrenia: familial neurocognitive measures

Objective: Early onset disorders may have more salient familial/genetic etiology. Neurocognitive deficits which are seen in families of adult onset schizophrenic patients were examined in healthy family members of patients with childhood-onset schizophrenia (COS). Methods: Trail Making Tests (TMT) A and B, Wechsler Intelligence Scale-Revised Digit Span and Vocabulary subtests were administered to 67 parents and 24 siblings of patients with childhood-onset schizophrenia and 114 healthy community controls (CC) comparable in sex, age, and educational level. Results: COS siblings performed significantly more poorly than did controls on Trails Making Test B with a trend for poorer performance evident on Trails Making Test A. COS parents performed more poorly than controls only on Trails Making Test A. Conclusions: Healthy first-degree relatives of COS probands have subtle deficits in tests involving oculomotor/psychomotor speed, working memory and executive function. This provides further support for continuity between COS and later onset schizophrenia and for a familial/genetic factor associated with the illness.

Neurocognitive impairments in nonpsychotic parents of children with schizophrenia and attention-deficit/hyperactivity disorder: the University of California, Los Angeles Family Study.

We tested the hypotheses that certain neurocognitive impairments index genetic liability to schizophrenia and that childhood-onset schizophrenia (COS) is a variant of adult-onset schizophrenia (AOS) by determining whether parents of COS probands show the types of neurocognitive impairments found in relatives of AOS probands. Parents of COS probands (n = 79) were compared with parents of attention-deficit/hyperactivity disorder (ADHD; n = 190) and community control (CC; n = 115) probands on 3 neurocognitive tasks shown in previous research to detect impairments in patients with AOS and ADHD and in the relatives of patients with AOS. Parents with a diagnosis of psychosis were excluded from the study. On the Degraded Stimulus-Continuous Performance Test and the Trail-Making Test B-Adolescent Version, the parents of COS probands performed significantly worse than the parents of CC and ADHD probands, who did not differ significantly from each other. On the Span of Apprehension, we found no significant group differences. Using rigorous cutoffs, a combination of scores on the 3 neurocognitive tests identified 16 (20%) of the mothers and fathers of COS probands compared with 0% of the mothers and fathers of CC probands. There was diagnostic specificity of the neurocognitive impairments. A combination of neurocognitive scores identified 6 (12%) of the mothers of COS probands vs 0% of the mothers of ADHD probands. A cutoff that identified 2 (2%) of the fathers of ADHD probands classified 5 (17%) of the fathers of COS probands. We found no significant differences in neurocognitive functions between the parents of ADHD and CC probands. The aggregation of neurocognitive impairments in the parents of COS probands provides further evidence of etiologic continuity between COS and AOS. A substantial subgroup of parents of COS probands had a worse neurocognitive performance than that of any of the parents of ADHD and CC probands. Receiver operating characteristic curves showed that when rigorous cutoffs define neurocognitive impairments, the combination of scores on certain neurocognitive tasks produced a level of diagnostic accuracy in the parents of COS probands that is sufficient for use in genetic linkage studies.