An online survey to understand the needs of caregivers of family members with 22q11 deletion syndrome.

BACKGROUND: Most individuals with 22q11.2 deletion syndrome (22q11DS) have multi-system and lifelong needs requiring substantial support. Their primary caregivers are usually family members who dedicate lifelong time and effort to their role. The pressures of their roles can negatively impact caregivers' psychosocial well-being, suggesting a need for additional support for this community who currently have no specialised interventions available. METHOD: This online study surveyed 103 caregivers of family members with 22q11DS to determine the barriers to accessing support that they faced, the kind of support they would value and whether an online intervention could meet their needs. RESULTS: The caregivers indicated that a brief online intervention focused on teaching practical skills and connecting them with a peer network of support would be most valuable. CONCLUSIONS: Future studies are planned that will build on these results by designing and testing online interventions tailored to this community.

The COVID-19 pandemic's impact on worry and medical disruptions reported by individuals with chromosome 22q11.2 copy number variants and their caregivers.

BACKGROUND: The world has suffered immeasurably during the COVID-19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic. METHODS: The University of Pennsylvania COVID-19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages. RESULTS: A total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID-19 had the highest average endorsed worry, whilst currently having COVID-19 had the lowest rated worry. Total COVID-19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID-19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID-19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged. CONCLUSIONS: Widespread medical care disruptions and pandemic-related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long-term effects of COVID-19 worries, interruptions to care and hospital avoidance require further study.

Neurocognition and adaptive functioning in a genetic high risk model of schizophrenia.

BACKGROUND: Identifying factors that influence the functional outcome is an important goal in schizophrenia research. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20-25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS. METHODS: We used comprehensive neurocognitive test data available for 99 adults with 22q11DS (n = 43 with schizophrenia) and principal component analysis to derive four domains of neurocognition (Verbal Memory, Visual and Logical Memory, Motor Performance, and Executive Performance). We then investigated the association of these neurocognitive domains with adaptive functioning using Vineland Adaptive Behavior Scales data and a linear regression model that accounted for the effects of schizophrenia status and overall intellectual level. RESULTS: The regression model explained 46.8% of the variance in functional outcome (p < 0.0001). Executive Performance was significantly associated with functional outcome (p = 0.048). Age and schizophrenia were also significant factors. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness. CONCLUSION: The findings provide the impetus for further studies to examine the potential of directed (early) interventions targeting Executive Performance to improve long-term adaptive functional outcome in individuals with, or at high risk for, schizophrenia. Moreover, the neurocognitive test profiles may benefit caregivers and clinicians by providing insight into the relative strengths and weaknesses of individuals with 22q11DS, with and without psychotic illness.

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis. METHODS: We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available. RESULTS: Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020). CONCLUSIONS: These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

Clinical experience with single-nucleotide polymorphism-based non-invasive prenatal screening for 22q11.2 deletion syndrome.

OBJECTIVES: To evaluate the performance of a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for the detection of fetal 22q11.2 deletion syndrome in clinical practice, assess clinical follow-up and review patient choices for women with high-risk results. METHODS: In this study, 21 948 samples were submitted for screening for 22q11.2 deletion syndrome using a SNP-based NIPT and subsequently evaluated. Follow-up was conducted for all cases with a high-risk result. RESULTS: Ninety-five cases were reported as high risk for fetal 22q11.2 deletion. Diagnostic testing results were available for 61 (64.2%) cases, which confirmed 11 (18.0%) true positives and identified 50 (82.0%) false positives, resulting in a positive predictive value (PPV) of 18.0%. Information regarding invasive testing was available for 84 (88.4%) high-risk cases: 57.1% (48/84) had invasive testing and 42.9% (36/84) did not. Ultrasound anomalies were present in 81.8% of true-positive and 18.0% of false-positive cases. Two additional cases were high risk for a maternal 22q11.2 deletion; one was confirmed by diagnostic testing and one had a positive family history. There were three pregnancy terminations related to screening results of 22q11.2 deletion, two of which were confirmed as true positive by invasive testing. CONCLUSIONS: Clinical experience with this SNP-based non-invasive screening test for 22q11.2 deletion syndrome indicates that these deletions have a frequency of approximately 1 in 1000 in the referral population with most identifiable through this test. Use of this screening method requires the availability of counseling and other management resources for high-risk pregnancies.

Pharmacological treatment of 22q11.2 deletion syndrome-related psychoses.

In their recent article in Pharmacopsychiatry Verhoeven and Egger report a case series of 28 patients and state that "treatment of psychotic symptoms in patients with 22q11.2 deletion syndrome (22q11.2DS) with quetiapine or clozapine in combination with valproic acid appears likely to be more effective than with other psychotropic compounds". In this letter, we discuss the limitations of their case series and the lack of evidence for such a sweeping conclusion. In lieu of strong evidence to the contrary, standard pharmacological treatments of psychotic illness in 22q11.2DS remains recommended, with attention to 22q11.2DS-related issues. The latter would include management strategies to help ameliorate the elevated risk of seizures (e. g. when using clozapine), and vigilance for Parkinson's disease or other potential movement disorders.

Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic subtype of intellectual disability (ID) remarkable for its constellation of congenital, developmental and later-onset features. Survival to adulthood is now the norm, and serious psychiatric illness is common in adults. However, little is known about the experiences and perceived needs of individuals with 22q11.2DS and their caregivers at time of transition from paediatric to adult models of care and beyond. METHOD: We administered a mail survey to 84 caregivers of adults with 22q11.2DS and 34 adult patients themselves, inquiring about medical and social services, perceived burden and major challenges in adulthood in 22q11.2DS. Standard quantitative and qualitative methods were used to analyse the responses. RESULTS: Fifty-three (63.1%) caregivers and 20 (58.8%) adults with 22q11.2DS completed the survey. Perceived burden was high, with psychiatric illness and/or behavioural issues considered the most challenging aspects of adulthood in 22q11.2DS by the majority of caregivers (70.0%) and many patients themselves (42.9%). Irrespective of the extent of ID and the presence or absence of other major features, caregivers expressed dissatisfaction with medical and social services for adults, including at time of transition from paediatric care. CONCLUSIONS: To our knowledge, this is the first study to examine the subjective experiences of adults with 22q11.2DS and their caregivers and to identify their perceived needs for services. Better awareness of 22q11.2DS and its later-onset manifestations, early diagnosis and treatment of psychiatric illness, additional support at time of transition and dedicated clinics for adults with 22q11.2DS may help to improve patient outcomes and reduce caregiver burden.

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Caregiver and adult patient perspectives on the importance of a diagnosis of 22q11.2 deletion syndrome.

BACKGROUND: Recent advances in genetics are particularly relevant in the field of intellectual disability (ID), where sub-microscopic deletions or duplications of genetic material are increasingly implicated as known or suspected causal factors. Data-driven reports on the impact of providing an aetiological explanation in ID are needed to help justify widespread use of new and expensive genetic technologies. METHODS: We conducted a survey of caregivers on the value of a genetic/aetiologic diagnosis of 22q11.2 deletion syndrome (22q11.2DS), the most common microdeletion syndrome in ID. We also surveyed the opinion of a high-functioning subset of adults with 22q11.2DS themselves. We used standard quantitative and qualitative methods to analyse the responses. RESULTS: In total, 73 of 118 surveys were returned (61.9%). There was convergence of quantitative and qualitative results, and consistency between adult patient and caregiver responses. A definitive molecular diagnosis of 22q11.2DS was a critical event with diverse positive repercussions, even if occurring later in life. Frequently cited benefits included greater understanding and certainty, newfound sense of purpose and a platform for advocacy, and increased opportunities to optimise medical, social and educational needs. CONCLUSIONS: This is the first study to characterise the impact of a diagnosis of this representative microdeletion syndrome on adult patients and their families. The results both validate and expand on the theoretical benefits proposed by clinicians and researchers. The use of genome-wide microarray technologies will provide an increasing number of molecular diagnoses. The importance of a diagnosis of 22q11.2DS demonstrated here therefore has implications for changing attitudes about molecular genetic diagnosis that could benefit individuals with ID of currently unknown cause and their families.

Neuropathologic features in adults with 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22qDS) is the most common microdeletion syndrome in humans. Its multisystem manifestations include congenital anomalies and neuropsychiatric disorders such as schizophrenia. Structural neuroimaging shows various abnormalities, but no postmortem brain studies exist. We report neuropathologic findings in 3 individuals from a cohort of 100 adults with a confirmed 22q11.2 deletion. All 3 had schizophrenia. Postmortem examination of Case 1, a 44-year-old male, revealed bilateral periventricular nodular heterotopia in the frontal lobes and ectopic neurons scattered throughout the frontal white matter. Cases 2 (male, aged 22 years) and 3 (female, 52 years) showed no evidence of migration abnormalities, but both had extensive astrocytic gliosis and focal collections of macrophages in the cerebral white matter, suggestive of cerebrovascular pathology. Review of magnetic resonance imaging findings available for 66 other subjects in the cohort revealed polymicrogyria in one and right cerebellar disorganization in another of the 26 subjects with schizophrenia. The results support previous neuroimaging reports suggesting that neuronal migration abnormalities may be a feature of 22qDS. Both early developmental brain abnormalities and fetal and later microvascular pathology may play a role in the pathogenesis of the neuropsychiatric phenotype of 22qDS, including white matter abnormalities and schizophrenia.

Premature death in adults with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disease with a prevalence of 1/4000. Variable expression of congenital and later onset features contributes to its under-recognition. Longevity in those surviving childhood is believed to be normal but data are limited. METHODS: We prospectively followed 264 subjects; 102 adults (>17 years) with 22q11.2DS (44 male (M), 58 female (F); mean (SD) age 33.6 (10.9) years) and their 162 unaffected siblings (77 M, 85 F; mean age 36.1 (12.2) years). We compared survival between groups using Kaplan-Meier estimates. RESULTS: Twelve (11.8%; 4 M, 8 F) individuals with 22q11.2DS and no siblings died (p<0.0001). Survival to ages 40 and 50 years was 89.9% and 73.9%, respectively. Median age at death was 41.5 (range 18.1-68.6) years. Deaths included two (7.7%) of 26 subjects with neither major congenital heart disease (CHD) nor schizophrenia. Four of six sudden and unexpected deaths occurred in individuals with no major CHD. There was no evidence of cancer or coronary artery disease or family history of sudden death in the 12 patients who died, six of whom had autopsies. DISCUSSION: Individuals with 22q11.2DS who survive childhood have diminished life expectancy and increased risk of sudden death not attributable to any single factor. Some sudden and/or premature deaths observed in the general population may represent undiagnosed 22q11.2DS. Increased recognition of the syndrome by family doctors, specialists and coroners will be essential to facilitate the tissue studies needed to determine underlying mechanisms.

Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22.

Schizophrenia is a complex disorder, and there is substantial evidence supporting a genetic etiology. Despite this, prior attempts to localize susceptibility loci have produced predominantly suggestive findings. A genome-wide scan for schizophrenia susceptibility loci in 22 extended families with high rates of schizophrenia provided highly significant evidence of linkage to chromosome 1 (1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage (lod) score of 6.50. This linkage result should provide sufficient power to allow the positional cloning of the underlying susceptibility gene.

Autism Spectrum and psychosis risk in the 22q11.2 deletion syndrome. Findings from a prospective longitudinal study.

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11DS) have a 25% risk for schizophrenia and related psychotic disorders. Some have hypothesized that Autism Spectrum Disorders (ASDs) diagnosed in children with 22q11DS may actually represent the social-communicative defects often observed during the early developmental stages of schizophrenia. METHODS: We prospectively studied 89 children with 22q11DS to test this hypothesis. At baseline, the Autism Diagnostic Interview was used to assess ASD, evaluating both current and early childhood behaviors. At follow-up, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to determine development of a psychotic disorder or psychotic symptoms. RESULTS: The average age (±SD) at first and last assessments was 14.3±1.9 and 19.0±3.0years, respectively. Nineteen (21.3%) children developed a psychotic disorder. Contrary to our hypothesis, there was no significant difference in the proportion that developed a psychotic disorder, comparing those with (n=9, 17.3%) and those without ASD at baseline (n=10, 27%; OR=0.500, 95% CI=0.160-1.569, p=0.235). Similar results were obtained using autistic symptom severity as quantitative predicting variable, psychotic symptoms as the outcome, and when correcting for age, gender and full scale IQ. CONCLUSION: Results indicate that in children with 22q11DS, early childhood autistic features are not associated with an increased risk for subsequent development of psychotic disorders or symptoms, replicating previous retrospective findings in adults with 22q11DS. These results indicate that ASD and psychotic disorders can emerge independently, as pleiotropic phenotypes in the context of 22q11DS.

The New York High-Risk Project. Psychoses and cluster A personality disorders in offspring of schizophrenic parents at 23 years of follow-up.

BACKGROUND: We herein present lifetime prevalence rates of psychoses and DSM-III-R cluster A personality disorders in sample A of the New York High-Risk Project, a prospective study following offspring of parents with schizophrenia (HRSz subjects) and affective illness (HRAff subjects) and of psychiatrically normal parents (NC subjects) from midchildhood to adulthood. METHODS: We interviewed the offspring in adulthood with the Schedule for Affective Disorders and Schizophrenia, Lifetime Version, for Axis I disorders and the Personality Disorder Examination for Axis II disorders. RESULTS: Lifetime prevalence rates (+/- SE) of schizophrenia and unspecified psychosis were 11.1% +/- 4.3% and 5.6% +/- 3.1%, respectively, in the HRSz group and 0% in the HRAff and NC groups. Rates of schizoaffective disorder subclassified as mainly schizophrenic, however, were highest in the HRAff group. Rates of psychotic affective disorders did not differ between the HRSz and other groups. Age-corrected morbidity risks were similar to lifetime prevalence rates. Rates of the three cluster A personality disorders did not differ among the groups, but the combined rate was greater in the HRSz and HRAff groups than in the NC group. CONCLUSIONS: Our data strongly support a specific familial liability to narrowly defined schizophrenia that is not shared by families of probands with affective disorder. Schizoaffective disorder and cluster A personality disorders, however, occur in families of both schizophrenic probands and probands with affective disorder. Psychotic affective disorders, which are not increased in HRSz subjects, do not appear to be an expression of the liability to schizophrenia.

The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up.

BACKGROUND: The New York High-Risk Project is a study of offspring of patients with schizophrenia (HRSz group) or affective illness (HRAff group) and psychiatrically normal parents (NC group) observed prospectively from childhood to adulthood. We herein present lifetime prevalence and comorbidity rates of Axis I disorders in subjects and their siblings from sample A of the project. METHODS: Schedule for Affective Disorders and Schizophrenia-Lifetime Version interviews conducted with the offspring in adulthood were used to obtain diagnoses of Axis I disorders. RESULTS: Schizophrenia and unspecified psychoses occurred only in the HRSz group. However, schizoaffective and psychotic affective disorders occurred equally in the HRSz and HRAff groups. Total rates of psychosis in these groups were significantly higher than in the NC group. All groups had similar rates of nonpsychotic affective and substance abuse disorders. The HRAff group, however, had significantly more total affective illness than the NC group and tended to have more anxiety disorders than the other groups. Comorbidity rates in the HRSz and HRAff groups were nearly twice those of the NC group. CONCLUSIONS: The familial liabilities to schizophrenia and affective disorders show specificities and commonalities, differing markedly from each other in their expression of some disorders and sharing others. Patterns of comorbidity are generally, although not entirely, similar to these liabilities.

22q11 deletion syndrome: a genetic subtype of schizophrenia.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (approximately 2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.

Temporal lobe abnormalities in multigenerational families with schizophrenia.

Brain structure in familial schizophrenia was studied with computerized tomography in 42 individuals from six multigenerational families. Sulcal enlargement in the lateral temporal cortex, and ventricular and cisternal enlargement in the medial temporal region were observed in psychotic individuals compared to unaffected family members. Genetic factors in familial schizophrenia may exert part of their effect through determining or altering temporal lobe structure.

Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia.

BACKGROUND: A genetic syndrome associated with schizophrenia, 22q11 deletion syndrome (22qDS), may represent a genetic subtype of schizophrenia (22qDS-Sz). Structural brain changes are common in schizophrenia and may involve developmental anomalies, but there are no data yet for 22qDS-Sz. The objective of this study was to assess brain structure in adults with 22qDS-Sz using magnetic resonance imaging (MRI). METHODS: Brain and arterial MRI scans of 11 adults with 22qDS-Sz (mean age = 28.4 years, SD = 6.5) were systematically assessed by a neuroradiologist for qualitative anomalies. RESULTS: A high frequency of abnormalities were found: T2 white matter bright foci (BF), 90%; developmental midline anomalies, 45%; cerebral atrophy or ventricular enlargement, 54%; mild cerebellar atrophy, 36%; skull base abnormalities, 55%; and minor vascular abnormalities, 36%. CONCLUSIONS: BF and skull base abnormalities, especially in association with neurodevelopmental midline abnormalities, may be distinguishing MRI features for a genetic subtype of schizophrenia involving a deletion on chromosome 22.

Impaired olfactory identification in relatives of patients with familial schizophrenia.

OBJECTIVE: Impaired olfactory identification ability has previously been demonstrated in patients with schizophrenia. This study assessed olfactory function in psychotic and nonpsychotic members of multigenerational families with familial schizophrenia to determine whether deficits were present in both groups. METHOD: The University of Pennsylvania Smell Identification Test was administered birhinally to three groups of subjects aged less than 65 years: 19 psychotic and 27 nonpsychotic members of families with familial schizophrenia and 43 age- and sex-matched healthy volunteers. RESULTS: Nonpsychotic family members had significantly higher mean University of Pennsylvania Smell Identification Test scores than psychotic family members but were impaired relative to the healthy volunteer group. These group differences could not be accounted for by age, sex, or smoking habit. Fifty-eight percent of the psychotic and 34% of the nonpsychotic family members performed in the microsmic (impaired) range, compared to 9% of the healthy volunteers. CONCLUSIONS: Impaired olfactory deficits may aggregate in families with schizophrenia and may be indicative of a genetic predisposition to psychosis.