DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination. Four patients with features including immunodeficiency and developmental and growth delay were found to have mutations in the gene encoding DNA ligase IV (LIG4). Their clinical phenotype closely resembles the DNA damage response disorder, Nijmegen breakage syndrome (NBS). Some of the mutations identified in the patients directly disrupt the ligase domain while others impair the interaction between DNA ligase IV and Xrcc-4. Cell lines from the patients show pronounced radiosensitivity. Unlike NBS cell lines, they show normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype is observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.

Small supernumerary marker chromosomes (SMCs) are present in about 0.05% of the human population. In approximately 30% of SMC carriers (excluding the approximately 60% SMC derived from one of the acrocentric chromosomes), an abnormal phenotype is observed. The clinical outcome of an SMC is difficult to predict as they can have different phenotypic consequences because of (1). differences in euchromatic DNA-content, (2). different degrees of mosaicism, and/or (3). uniparental disomy (UPD) of the chromosomes homologous to the SMC. Here, we present 35 SMCs, which are derived from all human chromosomes, apart from chromosome 6, as demonstrated by the appropriate molecular cytogenetic approaches, such as centromere-specific multicolor fluoresence in situ hybridization (cenM-FISH), multicolor banding (MCB), and subcentromere-specific multicolor FISH (subcenM-FISH). In nine cases without an aberrant phenotype, neither partial proximal trisomies nor UPD could be detected. Abnormal clinical findings, such as psychomotoric retardation and/or craniofacial dysmorphisms, were associated with seven of the cases in which subcentromeric single-copy probes were proven to be present in three copies. Conversely, in eight cases with a normal phenotype, proximal euchromatic material was detected as partial trisomy. UPD was studied in 12 cases and subsequently detected in two of the cases with SMC (partial UPD 4p and maternal UPD 22 in a der(22)-syndrome patient), indicating that SMC carriers have an enhanced risk for UPD. At present, small proximal trisomies of 1p, 1q, 2p, 6p, 6q, 7q, 9p, and 12q seem to lead to clinical manifestations, whereas partial proximal trisomies of 2q, 3p, 3q, 5q, 7p, 8p, 17p, and 18p may not be associated with significant clinical symptoms. With respect to clinical outcome, a classification of SMCs is proposed that considers molecular genetic and molecular cytogenetic characteristics as demonstrated by presently available methods.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5' of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Léri-Weill syndrome (LWS) or dyschondrosteosis represents a short stature syndrome characterised by the mesomelic shortening of the forearms and lower legs and by bilateral Madelung deformity of the wrists. Recently, mutations in the pseudoautosomal homeobox gene SHOX have been shown to be causative for this disorder. This gene has previously been described as the short stature gene implicated in Turner syndrome (TS). We studied 32 Léri-Weill patients from 18 different German and Dutch families and present clinical, radiological and molecular data. Phenotypic inter-and intrafamilial heterogeneity is a frequent finding in LWS, and phenotypic manifestations are generally more severe in females. In males, muscular hypertrophy is a frequent finding. To test for SHOX mutations we used FISH, Southern blot and SSCP analysis as well as long-range PCR and sequencing. We identified (sub)microscopic deletions encompassing the SHOX gene region in 10 out of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. We did not detect SHOX mutations in almost half (41%) the LWS families studied, which suggests different genetic etiologies.

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