Eva W.C. Chow

Clinical features of 78 adults with 22q11 Deletion Syndrome.

22q11 Deletion Syndrome (22q11DS) is a common microdeletion syndrome with multisystem expression. Phenotypic features vary with age, ascertainment, and assessment. We systematically assessed 78 adults (36 M, 42 F; mean age 31.5, SD 10.5 years) with a 22q11.2 deletion ascertained through an adult congenital cardiac clinic (n = 35), psychiatric‐related sources (n = 39), or as affected parents of subjects (n = 4). We recorded the lifetime prevalence of features requiring attention, with 95% confidence intervals (CI) not overlapping zero. Subtle learning difficulties, hypernasality and facial gestalt were not included. We investigated ascertainment effects using non‐overlapping subgroups ascertained with tetralogy of Fallot (n = 31) or schizophrenia (n = 31). Forty‐three features met inclusion criteria and were present in 5% or more patients, including several of later onset (e.g., hypothyroidism, cholelithiasis). Number of features per patient (median 9, range 3–22) correlated with hospitalizations (P = 0.0002) and, when congenital features were excluded, with age (P = 0.02). Adjusting for ascertainment, 25.8% (95% CI, 9.5–42.1%) of patients had cardiac anomalies and 22.6% (95% CI, 7.0–38.2%) had schizophrenia. Ascertainment subgroups were otherwise similar in median number and prevalence of features. Non‐characteristic features are common in 22q11DS. Adjusting for ascertainment effects is important. Many treatable conditions may be anticipated and features may accumulate over time. The results have implications for clinical assessment and management, genetic counseling and research into pathophysiological mechanisms.

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.

Linkage of Familial Schizophrenia to Chromosome 13q32

Over the past 4 years, a number of investigators have reported findings suggestive of linkage to schizophrenia, with markers on chromosomes 13q32 and 8p21, with one recent study by Blouin et al. reporting significant linkage to these regions. As part of an ongoing genome scan, we evaluated microsatellite markers spanning chromosomes 8 and 13, for linkage to schizophrenia, in 21 extended Canadian families. Families were analyzed under autosomal dominant and recessive models, with broad and narrow definitions of schizophrenia. All models produced positive LOD scores with markers on 13q, with higher scores under the recessive models. The maximum three-point LOD scores were obtained under the recessive-broad model: 3.92 at recombination fraction (theta).1 with D13S793, under homogeneity, and 4.42 with alpha=.65 and straight theta=0 with D13S793, under heterogeneity. Positive LOD scores were also obtained, under all models, for markers on 8p. Although a maximum two-point LOD score of 3.49 was obtained under the dominant-narrow model with D8S136 at straight theta=0.1, multipoint analysis with closely flanking markers reduced the maximum LOD score in this region to 2. 13. These results provide independent significant evidence of linkage of a schizophrenia-susceptibility locus to markers on 13q32 and support the presence of a second susceptibility locus on 8p21.

Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.

Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11.2DS) is a common microdeletion syndrome with congenital and late-onset features. Testing for the genomic content of copy number variations (CNVs) may help elucidate the 22q11.2 deletion mechanism and the variable clinical expression of the syndrome including the high (25%) risk for schizophrenia. We used genome-wide microarrays to assess CNV content and the parental origin of 22q11.2 deletions in a cohort of 100 adults with 22q11.2DS (44 with schizophrenia) and controls. 22q11.2DS subjects with schizophrenia failed to exhibit de novo CNVs or any excess of novel inherited CNVs outside the 22q11.2 region. There were no significant effects of parental origin of the 22q11.2 deletion, deletion length, parental age or family history on expression of schizophrenia. There was no evidence for a general increase of de novo CNVs in 22q11.2DS. A novel finding was the relative paucity of males with de novo 22q11.2 deletions of paternal origin (P = 0.019). The Y chromosome may play a mediating role in the mechanism of 22q11.2 deletion events during spermatogenesis, resulting in the previously observed excess of maternal de novo 22q11.2 deletions. Hemizygosity of the 22q11.2 region appears to be the major CNV-related risk factor for schizophrenia in 22q11.2DS. The results reinforce the need for further efforts to identify specific molecular mechanisms underlying this expression and to identify the 1% of patients with schizophrenia who carry 22q11.2 deletions.

Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22.

Previously, we have reported linkage of markers from chromosome 1q22 to schizophrenia, a finding supported by several independent studies. We have now examined the region of strongest linkage for evidence of linkage disequilibrium (LD) in a sample of 24 Canadian familial-schizophrenia pedigrees. Analysis of 14 microsatellites and 15 single-nucleotide polymorphisms (SNPs) from the 5.4-Mb region between D1S1653 and D1S1677 produced significant evidence (nominal P<.05) of LD between schizophrenia and 2 microsatellites and 6 SNPs. All of the markers exhibiting significant LD to schizophrenia fall within the genomic extent of the gene for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON), making it a prime positional candidate for the schizophrenia-susceptibility locus on 1q22, although initial mutation analysis of this gene has not identified any schizophrenia-associated changes within exons. Consistent with several recently identified candidate genes for schizophrenia, CAPON is involved in signal transduction in the NMDA receptor system, highlighting the potential importance of this pathway in the etiology of schizophrenia.

Neurocognitive profile in 22q11 deletion syndrome and schizophrenia

OBJECTIVE Schizophrenia is associated with neurocognitive deficits, but its etiologic heterogeneity may complicate the delineation of a neurocognitive profile. Schizophrenia associated with 22q11 Deletion Syndrome (22qDS) represents a more genetically homogeneous subtype for study. We hypothesized that in adults with 22qDS the neurocognitive profiles would differ between those with and without schizophrenia. METHOD Using a comprehensive battery of tests, we compared the neurocognitive performance profiles in those with schizophrenia (n=27; 14 M, 13 F; mean age=30.6 years, SD=7.7 years) and those with no history of psychosis (n=29; 16 M, 13 F; mean age=25.0 years, SD=9.0 years). RESULTS The 22qDS groups with and without schizophrenia had similar mean estimated IQ (71.6, SD=8.2 and 74.8, SD=6.1, respectively) and academic achievement, however the neurocognitive profiles of the two groups differed significantly on multivariate analysis (F(24,31)=2.25, p=0.017). The group with schizophrenia performed significantly more poorly on tests of motor skills, verbal learning, and social cognition (effect sizes>or=0.8) after correction for multiple comparisons. Other tests, but not the attentional measures used, showed nominally significant differences. CONCLUSIONS In adults with 22qDS, the pattern of neurocognitive differences between those with and without schizophrenia appears similar to that between patients with schizophrenia and controls. Attentional dysfunction may be a more general feature of 22qDS. The findings support 22qDS-schizophrenia as a genetic model for neurodevelopmental investigations of schizophrenia.

Phenotype of adults with the 22q11 deletion syndrome: A review.

22q11 deletion syndrome (22qDS) is due to microdeletions of chromosome region 22q11.2. Little is known about the phenotype of adults. We reviewed available case reports of adults (age >/=18 years) with 22qDS and compared the prevalence of key findings to those reported in a large European survey of 22qDS (497 children and 61 adults) [Ryan et al., 1997: J. Med. Genet. 34:798-804]. Fifty-five studies reported on 126 adults (83 women, 40 men, 3 unknown sex), mean age 29.6 years (SD = 8.7 years). Compared with the European survey, adults with 22qDS reviewed had a lower rate of CHD, 30% versus 75%; chi(2) = 88.65, df = 1, P < 0.0001, but higher rates of identified palate anomalies, 88% versus 15%; chi(2) = 37.45, df = 1, P < 0.0001, and learning difficulties, 94% versus 79%; chi(2) = 12.13, df = 1, P = < 0.0008. The most common finding reported was minor facial anomalies. Few reports provided details of minor physical anomalies. Psychiatric conditions were more prevalent, 36% versus 18%; chi(2)= 5.71, df = 1, P < 0.02, than in the survey: 60% of reviewed adults were transmitting parents (72% mothers) ascertained following diagnosis of affected offspring. They had lower rates of CHD, cleft palate, and psychiatric disorders but similar rates of learning disabilities, and other palate and facial anomalies compared with adults ascertained by other methods. The results suggest that learning disabilities and facial and palate anomalies may be key findings in 22qDS adults, but that ascertainment is a key factor in the observed phenotype. Comprehensive studies of adults with 22qDS identified independently of familial transmission are necessary to further delineate the phenotype of adults and to determine the natural history of the syndrome.

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.

Chromosomal Abnormalities and Schizophrenia

Schizophrenia is a common and serious psychiatric illness with strong evidence for genetic causation, but no specific loci yet identified. Chromosomal abnormalities associated with schizophrenia may help to understand the genetic complexity of the illness. This paper reviews the evidence for associations between chromosomal abnormalities and schizophrenia and related disorders. The results indicate that 22q11.2 microdeletions detected by fluorescence in-situ hybridization (FISH) are significantly associated with schizophrenia. Sex chromosome abnormalities seem to be increased in schizophrenia but insufficient data are available to indicate whether schizophrenia or related disorders are increased in patients with sex chromosome aneuploidies. Other reports of chromosomal abnormalities associated with schizophrenia have the potential to be important adjuncts to linkage studies in gene localization. Advances in molecular cytogenetic techniques (i.e., FISH) have produced significant increases in rates of identified abnormalities in schizophrenia, particularly in patients with very early age at onset, learning difficulties or mental retardation, or dysmorphic features. The results emphasize the importance of considering behavioral phenotypes, including adult onset psychiatric illnesses, in genetic syndromes and the need for clinicians to actively consider identifying chromosomal abnormalities and genetic syndromes in selected psychiatric patients.