We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22qll. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month ofbirth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters. (JMed Genet 1997;34:798-804) Data collectionParticipating centres from Europe were sent data questionnaires relating to cases of proven deletions within chromosome band 22ql 1. The probes and microsatellite markers used varied between centres but all mapped within the DGS region.2 Centres were asked to send information on all their cases, whether previously published or not. The data for all UK centres was collected by one person (AR) who also entered information into the database from the returned questionnaires. Data were requested on heart, palate, renal, and thymus abnormalities, parathyroid function, growth, developmental status, behaviour, and psychiatric illness. All available patient information was entered into an anonymous central database. Some questionnaires did not provide information on all sections, for example, the heart section was completed in more questionnaires than the renal section. Hence, the total number of patients for which data were recorded is specified in each section of the results.

Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.

SummaryAlthough autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants.

Autosomal recessive spinal muscular atrophy (SMA) is classified, on the basis of age at onset and severity, into three types: type I, severe; type II, intermediate; and type III, mild. The critical region in 5q13 contains an inverted repeat harboring several genes, including the survival motor neuron (SMN) gene, the neuronal apoptosis inhibitory protein (NAIP) gene, and the p44 gene, which encodes a transcription-factor subunit. Deletion of NAIP and p44 is observed more often in severe SMA, but there is no evidence that these genes play a role in the pathology of the disease. In > 90% of all SMA patients, exons 7 and 8 of the telomeric SMN gene (SMNtel) are not detectable, and this is also observed in some normal siblings and parents. Point mutations and gene conversions in SMNtel suggest that it plays a major role in the disease. To define a correlation between genotype and phenotype, we mapped deletions, using pulsed-field gel electrophoresis. Surprisingly, our data show that mutations in SMA types II and III, previously classed as deletions, are in fact due to gene-conversion events in which SMNtel is replaced by its centromeric counterpart, SMNcen. This results in a greater number of SMNcen copies in type II and type III patients compared with type I patients and enables a genotype/phenotype correlation to be made. We also demonstrate individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explains why no consensus map of this region has been produced. This DNA variation may be due to a midisatellite repeat array, which would promote the observed high deletion and gene-conversion rate.

The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation.