Christel Huysmans

The neurobeachin gene is disrupted by a translocation in a patient with idiopathic autism

Autism is a developmental disorder characterised by a triad of clearly abnormal or impaired development in social interaction and communication, and a markedly restricted repertoire of activity and interests.1 Its incidence is estimated at about 1/1000 to 1/2000.2 Different metabolic and structural brain anomalies have been observed in subjects with autism but these data have not yet led to a single unifying theory on its pathogenesis. In a minority (5–10%) of cases, autism is a symptom of a recognisable disorder such as fragile X syndrome, tuberous sclerosis, or untreated phenylketonuria.3 However, the molecular pathways involved in these disorders have also not contributed to an increased understanding of the pathogenesis of autism. In the majority of cases, the cause of autism is not known but there is strong evidence for a genetic cause. A polygenic inheritance is likely but estimates on the number of interacting genes vary from two to 10.4,5 Moreover, it is likely that different combinations of genes are implicated in unrelated subjects.6 The identification of genes involved in autism is expected to increase our understanding of the pathogenesis of this disorder. Several large scale linkage studies and follow up analyses have yielded suggestive linkage to several different chromosomal regions. However, neither this approach nor the large number of association studies using candidate genes has resulted in the identification of autism susceptibility genes.5 As an alternative approach to identifying candidate genes for autism, we initiated a positional cloning strategy starting with subjects with autism carrying a de novo chromosomal anomaly. In a group of 525 subjects with autism who were karyotyped and had no recognised underlying medical condition, four were found to carry such a de novo chromosomal aberration. In none of them was there a family history of autism. Three had …

PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse

Heterotaxia is an aetiologically heterogeneous condition caused by an abnormal left-right axis formation, resulting in reversed left-right polarity of one or more organ systems. In a patient with heterotaxia and a de novo reciprocal translocation t(6;18)(q21;q21), we found that the PA26 gene was disrupted by the 6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26 gene in an Epstein-Barr virus-transformed cell line of this patient. During early embryogenesis of Xenopus, the orthologue of PA26, XPA26 is exclusively expressed in the notochord, a midline structure. This further supports a possible role of PA26 in human situs determination. Mutation analysis of human PA26 gene in 40 unrelated individuals with unexplained heterotaxia failed to identify mutations, indicating that PA26 mutations are not a frequent cause of heterotaxia in humans. Analysis of the PA26 gene structure resulted in the identification of a novel PA26-related gene family, which we have named the sestrin family, and which comprises three closely related genes in human and in mouse.

Mapping of the translocation breakpoints of primary pleomorphic adenomas and lipomas within a common region of chromosome 12.

Recent molecular cytogenetic analysis of uterine leiomyoma cell lines with chromosomal aberrations of 12q14-q15 have indicated that the chromosome 12 breakpoints cluster in a 445-kb region designated ULCR12 (uterine leiomyoma cluster region of the chromosome 12 breakpoints). Here we report the results of FISH studies of five primary pleomorphic adenomas and six primary lipomas and established cell lines of these tumor types characterized by translocations involving the chromosomal segment 12q13-q15. The results reveal that for nearly all tumors and cell lines analyzed, the chromosome 12 breakpoints map within a 350-kb region included in ULCR12, despite the previous cytogenetic assignment of the breakpoints to different bands of that region. In some cases the primary material and additionally analyzed cell lines allowed an even more precise localization of the breakpoints to less than 100 kb. Furthermore, a previously hidden translocation of ULCR12 in one primary tumor could be detected by FISH.

Involvement of a palindromic chromosome 22-specific low-copy repeat in a constitutional t(X; 22)(q27;q11)

Segmental duplications or low‐copy repeats (LCRs) on chromosome 22q11 have been implicated in several chromosomal rearrangements. The presence of AT‐rich regions in these duplications may lead to the formation of hairpin structures, which facilitate chromosomal rearrangement. Here we report the involvement of such a low‐copy repeat in a t(X;22) associated with a neural tube defect. Molecular analysis of the chromosomal breakpoints revealed that the chromosome 22 breakpoint maps in the palindromic non‐AT‐rich NF1‐like region of low‐copy repeat B (LCR‐B). No palindromic region was encountered near the breakpoint on chromosome X. Our findings confirm that there is no single mechanism leading to translocations with chromosome 22q11 involvement. Because LCR‐B does not contain genes involved in neural tube development, we believe that the gene responsible for the observed phenotype is most likely localized on chromosome X.

Carpal and tarsal synostoses and transverse reduction defects of the toes in two brothers heterozygous for a double de novo NOGGIN mutation

We describe two siblings with carpal and tarsal synostoses associated with transverse deficiencies of the toes. Mutation analysis of the NOG gene revealed a double missense mutation in both boys resulting in Pro42Ala and Pro50Arg. The parents were clinically unaffected, and these two mutations were not detected in their white blood cells or buccal mucosa. This indicates the presence of gonadal mosaicism or a low level of somatic mosaicism in one of the parents.

A novel NOG mutation Pro37Arg in a family with tarsal and carpal synostoses.

Noggin, an antagonist of members of the transforming growth factor-b family, plays an important role in joint morphogenesis. Mutations in the human Noggin gene, NOG, have been identified in sporadic and familial cases with disorders affecting joint formation. Proximal symphalangism (SYM1, OMIM 185800) is characterized by early onset progressive ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusions, and conductive hearing loss. In multiple synostosis syndrome (SYNS1, OMIM 186500) affected individuals share some clinical symptoms with SYM1 and have in addition brachydactyly, hypoplastic or absent middle phalanges, dislocation of the radial head, pectus carinatum, and a broad hemicylindrical nose. Individuals with tarsal/carpal coalition syndrome (TCC, OMIM 186570) have a