Identification of Neuropsychiatric Copy Number Variants in a Health Care System Population.

Importance: Population screening for medically relevant genomic variants that cause diseases such as hereditary cancer and cardiovascular disorders is increasing to facilitate early disease detection or prevention. Neuropsychiatric disorders (NPDs) are common, complex disorders with clear genetic causes; yet, access to genetic diagnosis is limited. We explored whether inclusion of NPD in population-based genomic screening programs is warranted by assessing 3 key factors: prevalence, penetrance, and personal utility. Objective: To evaluate the suitability of including pathogenic copy number variants (CNVs) associated with NPD in population screening by determining their prevalence and penetrance and exploring the personal utility of disclosing results. Design, Setting, and Participants: In this cohort study, the frequency of 31 NPD CNVs was determined in patient-participants via exome data. Associated clinical phenotypes were assessed using linked electronic health records. Nine CNVs were selected for disclosure by licensed genetic counselors, and participants' psychosocial reactions were evaluated using a mixed-methods approach. A primarily adult population receiving medical care at Geisinger, a large integrated health care system in the United States with the only population-based genomic screening program approved for medically relevant results disclosure, was included. The cohort was identified from the Geisinger MyCode Community Health Initiative. Exome and linked electronic health record data were available for this cohort, which was recruited from February 2007 to April 2017. Data were collected for the qualitative analysis April 2017 through February 2018. Analysis began February 2018 and ended December 2019. Main Outcomes and Measures: The planned outcomes of this study include (1) prevalence estimate of NPD-associated CNVs in an unselected health care system population; (2) penetrance estimate of NPD diagnoses in CNV-positive individuals; and (3) qualitative themes that describe participants' responses to receiving NPD-associated genomic results. Results: Of 90 595 participants with CNV data, a pathogenic CNV was identified in 708 (0.8%; 436 women [61.6%]; mean [SD] age, 50.04 [18.74] years). Seventy percent (n = 494) had at least 1 associated clinical symptom. Of these, 28.8% (204) of CNV-positive individuals had an NPD code in their electronic health record, compared with 13.3% (11 835 of 89 887) of CNV-negative individuals (odds ratio, 2.21; 95% CI, 1.86-2.61; P < .001); 66.4% (470) of CNV-positive individuals had a history of depression and anxiety compared with 54.6% (49 118 of 89 887) of CNV-negative individuals (odds ratio, 1.53; 95% CI, 1.31-1.80; P < .001). 16p13.11 (71 [0.078%]) and 22q11.2 (108 [0.119%]) were the most prevalent deletions and duplications, respectively. Only 5.8% of individuals (41 of 708) had a previously known genetic diagnosis. Results disclosure was completed for 141 individuals. Positive participant responses included poignant reactions to learning a medical reason for lifelong cognitive and psychiatric disabilities. Conclusions and Relevance: This study informs critical factors central to the development of population-based genomic screening programs and supports the inclusion of NPD in future designs to promote equitable access to clinically useful genomic information.

Postnatal nutritional treatment of neurocognitive deficits in fetal alcohol spectrum disorder.

Ethanol is the most important teratogen agent in humans. Prenatal alcohol exposure can lead to a wide range of adverse effects, which are broadly termed as fetal alcohol spectrum disorder (FASD). The most severe consequence of maternal alcohol abuse is the development of fetal alcohol syndrome, defined by growth retardation, facial malformations, and central nervous system impairment expressed as microcephaly and neurodevelopment abnormalities. These alterations generate a broad range of cognitive abnormalities such as learning disabilities and hyperactivity and behavioural problems. Socioeconomic status, ethnicity, differences in genetic susceptibility related to ethanol metabolism, alcohol consumption patterns, obstetric problems, and environmental influences like maternal nutrition, stress, and other co-administered drugs are all factors that may influence FASD manifestations. Recently, much attention has been paid to the role of nutrition as a protective factor against alcohol teratogenicity. There are a great number of papers related to nutritional treatment of nutritional deficits due to several factors associated with maternal consumption of alcohol and with eating and social disorders in FASD children. Although research showed the clinical benefits of nutritional interventions, most of work was in animal models, in a preclinical phase, or in the prenatal period. However, a minimum number of studies refer to postnatal nutrition treatment of neurodevelopmental deficits. Nutritional supplementation in children with FASD has a dual objective: to overcome nutritional deficiencies and to reverse or improve the cognitive deleterious effects of prenatal alcohol exposure. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of simultaneous multiple-nutrient supplementation.

Social isolation stress down-regulates cortical early growth response 1 (Egr-1) expression in mice.

Social isolation stress induces behavioral disturbances such as aggression, cognitive impairments, and deficits in prepulse inhibition in mice. Social isolation mice have, therefore, been studied as an animal model of neuropsychiatric disorders such as schizophrenia. Recently, the decrease in early growth response (Egr) gene expression levels were reported in the post-mortem brains of schizophrenia patients. In this study, we investigate the effects of social isolation stress on the expression levels of Egr mRNA and protein in the frontal cortex. Social isolation stress exposure significantly down-regulated the expression of Egr-1 protein and Egr-1 gene transcript in nucleus of cortical neurons in a manner dependent on a social isolation period. This stress had no effect on the expression level of Egr-1 in the striatum or the expression levels of other Egr family members (Egr-2, -3, and -4) in the frontal cortex. These results suggest that the decrease in Egr-1 expression in the frontal cortex may be involved in social isolation stress-induced behavioral abnormalities.

Rapid cycling in severely multidisabled children: a form of bipolar affective disorder?

A debilitating, regularly recurring, biphasic disorder is described in 6 severely multidisabled children. It was characterized by several days of lethargy, withdrawal, loss of abilities, irritability, and hypersomnolence followed or preceded by a high-energy state for several days during which the children slept very little, at times were euphoric, had improved mental ability, and were hyperactive. These cyclic episodes had been present for years but unexpectedly disappeared in one child. The etiology is unknown, in spite of detailed neurologic, metabolic, and endocrine investigations. All patients had family histories positive for affective disorder. Melatonin treatment helped to regulate the coexisting chronic sleep disorders of 3 children but failed to eliminate the cycles. Antiepileptic drug treatment, lithium, sedatives, stimulants, tranquilizers, and light therapy were largely ineffective. The children's symptoms and signs fit the diagnostic criteria of a bipolar affective illness, as it was modified for patients with associated neurologic disability; therefore, the patients appeared to have a unique disorder that closely resembles or is a variant of rapid cycling affective disorder.

Obsessive-compulsive disorder in Huntington's disease.

Two patients with Huntington's disease (HD) and obsessive-compulsive disorder (OCD) are reported. The OCD was manifested by repetitive, stereotyped, complex, egodystonic behaviors that were disabling. These cases and other neurological syndromes with OCD (Gilles de la Tourette syndrome, neuroacanthocytosis, postencephalitic parkinsonism, caudate infarction, carbon monoxide poisoning, manganese intoxication, anoxia, progressive supranuclear palsy, Sydenham's chorea, and frontal lobe lesions) indicate that the frontal lobe, caudate nucleus, and globus pallidus are members of a complex circuit that plays a key role in mediating the symptoms of OCD. Evidence of excitatory subcortical output to cortex is shared by many neurological disorders manifesting OCD.

Dominant olivopontocerebellar atrophy with dementia and extrapyramidal signs: report of a family through three generations.

The olivopontocerebellar atrophies (OPCA) can be divided into five disease entities. One of these, dominant OPCA with dementia and extrapyramidal signs, is better defined by the family we studied. Five persons in three generations were affected by progressive ataxia, tremor, rigidity and mental deterioration, beginning in their twenties and thirties. Neurologic examination showed mental deterioration, high-pitched dysarthric voice, gaze paresis, rigidity and coarse tremor. This disease differs from other dominant and recessive OPCAs clinically because of the prominent mental deterioration and extrapyramidal signs, and pathologically because of cortical, lentiform and substantia nigra neuronal loss.