A patient with autistic disorder and a 20/22 chromosomal translocation.

The case history of a 3-year-old boy without speech and who met 10 criteria of an autistic condition (DSM-IV) (American Psychiatric Association 1994) is reported. Psychometric evaluation, excluding the verbal scale, resulted in an IQ score of 56. The cytogenetic study showed a 20/22 translocation and an interstitial deletion within the region 22q11: 45,XY, -22, +der(20), t(20;22) (q13.3;q11.2), which was confirmed by fluorescence in situ hybridisation (FISH). Although deletions at 22q11 are responsible for the DiGeorge syndrome; clinical, metabolic, and neurological image studies of the patient were inconsistent with this syndrome. In the clinical examination the patient presented with a mildly dysmorphic facies, pectus excavatum, and a short thumb. A 99mTc HMPAO brain perfusion SPECT showed a hypoperfusion of the left temporoparietal cortex. As there have been no previous reports of autistic patients with abnormalities involving both chromosomes 20 and 22, these findings merit some discussion either as a possible cause of autism or as accompanying factors.

Cloning, chromosome mapping and expression analysis of the HIRA gene from Drosophila melanogaster.

The human HIRA gene was identified as a putative transcriptional regulator mapping within the DiGeorge syndrome critical region at 22q11. HIRA-related proteins have been described in a number of species, but functional information concerning family members is only available in Saccharomyces cerevisiae, where the Hir1p and Hir2p proteins are known to be transcriptional corepressors. In order to analyse conservation of HIRA-related genes and to provide resources for functional studies in another model organism we have isolated the HIRA gene from Drosophila melanogaster (dhira). The 3374 nucleotide cDNA encodes a protein of 1047 aa, showing 42% identity with the human protein. Alignment with the predicted HIRA proteins from human, mouse, chick and pufferfish reveals strong conservation within the N-terminal region which contains seven WD domains, with less conservation of C-terminal sequences. In situ hybridisation to salivary gland chromosomes indicates that the gene resides in region 7B2-3 of the X chromosome. Dhira is expressed through embryonic development and at lower levels during larval and pupal development. The expression of dhira is dramatically increased in early embryos and in females, suggesting that the dhira mRNA could be maternally deposited in the embryos.

Isolation and genomic characterization of the TUPLE1/HIRA gene of the pufferfish Fugu rubripes.

In an effort to obtain a small genomic construct for the generation of a HIRA transgenic mouse, we have isolated and sequenced the Fugu TUPLE1/HIRA gene. We have compared the gene organization and the proteins encoded in pufferfish and human and also searched for conserved DNA sequences that might be important in gene regulation. The pufferfish gene spans approx. 9 kb, which is approx. 11 times smaller than the human gene, owing to the reduced size of the introns. Like its human counterpart, it is organized into 25 exons. The majority of the splice sites are in identical positions to those found in the human gene, however, for three internal exons the positions of the splice sites are not directly comparable. The coding regions are almost identical in size and show a high degree of similarity, especially at the amino and carboxy termini. Comparisons of 5' and 3' sequences failed to detect similarities or sequences involved in regulation.

Haplotype analysis of 94 cystic fibrosis mutations with seven polymorphic CFTR DNA markers.

We have analyzed 416 normal and 467 chromosomes carrying 94 different cystic fibrosis (CF) mutations with polymorphic genetic markers J44, IVS6aGATT, IVS8CA, T854, IVS17BTA, IVS17BCA, and TUB20. The number of mutations found with each haplotype is proportional to its frequency among normal chromosomes, suggesting that there is no preferential haplotype in which mutations arise and thus excluding possible selection for specific haplotypes. While many common mutations in the worldwide CF population showed absence of haplotype variation, indicating their recent origins, some mutations were associated with more than one haplotype. The most common CF mutations, delta F508, G542X, and N1303K, showed the highest number of slippage events at microsatellites, suggesting that they are the most ancient CF mutations. Recurrence was probably the case for 9 CF mutations (R117H, H199Y, R347YH, R347P, L558S, 2184insA, 3272-26A-->G, R1162X, and 3849 + 10kbC-->T). This analysis of 94 CF mutations should facilitate mutation screening and provides useful data for studies on population genetics of CF.

Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W, a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences.

We present the genotype/phenotype correlation analysis for 16 cystic fibrosis (CF) patients who carry mutation R334W. Current age and age of diagnosis was significantly higher in the R334W/any-mutation group (P < 0.05 and P < 0.01), compared with the delta F508/delta F508 group. A slightly, but not significantly, worse lung function was found in the R334W/any-mutation group, when compared with the delta F508/delta F508 patients. The proportion of patients with lung colonization with bacterial pathogens was slightly, but not significantly, higher in the R334W/any-mutation group (71.4%), compared with the delta F508/delta F508 or R334W/delta F508 groups (55.5%). None of the R334W patients had meconium ileus but 60% were pancreatic insufficient (PI), a significantly lower proportion (P << 0.001) than delta F508/delta F508 patients. Two R334W/N1303K compound heterozygous sisters of three sibs with genotype R334W/delta F508 showed interfamilial discordant clinical data for lung and pancreatic function. The data provided here for mutation R334W demonstrate that this mutation is responsible for a less severe form of CF than delta F508. Interfamilial differences for PI and lung function suggest that other factors, viz. genetic, environmental and medical, contribute to the wide spectrum of clinical differences observed in CF patients with the same CF transmembrane conductance regulator genotypes.

Independent origins of cystic fibrosis mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T provide evidence of mutation recurrence in the CFTR gene.

Microsatellite analysis of chromosomes carrying particular cystic fibrosis mutations has shown different haplotypes in four cases: R334W, R347P, R1162X, and 3849 + 10kbC-->T. To investigate the possibility of recurrence of these mutations, analysis of intra- and extragenic markers flanking these mutations has been performed. Recurrence is the most plausible explanation, as it becomes necessary to postulate either double recombinations or single recombinations in conjunction with slippage at one or more microsatellite loci, to explain the combination of mutations and microsatellites if the mutations arose only once. Also in support of recurrence, mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T involve CpG dinucleotides, which are known to have an increased mutation rate. Although only 15.7% of point mutations in the coding sequence of CFTR have occurred at CpG dinucleotides, approximately half of these CpG sites have mutated at least once. Specific nucleotide positions of the coding region of CFTR, distinct from CpG sequences, also seem to have a higher mutation rate, and so it is possible that the mutations observed are recurrent. G-->A transitions are the most common change found in those positions involved in more than one mutational event in CFTR.