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These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.

Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominal P -values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013).

A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism. Molecular Psychiatry Molecular Psychiatry (2002) 7, 302-310.

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Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.

Smears obtained from 795 patients with suspicious thyroid nodules by fine needle aspiration (FNA) of the thyroid gland were seen over a 5-year period at the UCLA Center for the Health Sciences. From 72 patients who underwent subsequent surgical excision of their nodules, inadequate or discrepant FNA diagnoses were noticed in 20 cases (27.8%). These errors could be attributed to inadequate material for diagnosis (n = 6), sampling errors (n = 2), and cytodiagnostic errors (n = 12). If the diagnosis of follicular neoplasm was treated as indeterminate for malignancy, the overall efficiency of FNA was 88.9%. All false-negative diagnoses were related to procedure (i.e., inadequate smears or missed sampling of the lesion). The frequency of inadequate smears, in turn, was strongly related to the type of physician performing the aspiration. The frequency was highest among community-based clinicians (32.4%) and lowest among hospital-based cytopathologists (6.4%). With adequate sampling, the finding of 100% sensitivity in the diagnosis of malignant neoplasms by FNA cytology reaffirms its role as the procedure of choice in the initial screening of thyroid nodules.

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