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Deletions within 11q12.3-11q13.1 are very rare and to date only two cases have been described in the literature. In this study we describe a 23-year-old male patient with intellectual disability, behavioral problems, dysmorphic features, dysphagia, gastroesophageal reflux and skeletal abnormalities. Cornelia de Lange syndrome (CdLS, OMIM #122470; #300590; #610759; #300882; #614701) was suggested as a differential diagnosis in childhood although he lacked some of the features typical for this disorder. He does not have a mutation in any of the five known CdLS genes (NIPBL, SMC1A, SMC3, HDAC8, RAD21), but a 1.6Mb deletion at chromosome region 11q12.3-11q13.1 was detected by chromosome microarray. The deletion contains several genes including PPP2R5B, which has been associated with intellectual disability and overgrowth; NRXN2, which has been associated with intellectual disability and autism spectrum disorder; and CDCA5, which is part of the cohesin pathway, as are all the five known CdLS genes. It is therefore possible that deletion of CDCA5 may account for some of the CdLS like features of the present case.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with a strong genetic etiology; however, finding of candidate genes is hampered by its genetic heterogeneity and the influence of non-genetic factors on disease pathogenesis. We report a case of a male patient with GTS, obsessive compulsive disorder, attention-deficit/hyperactivity-disorder, as well as other comorbidities, and a translocation t(3;9)(q25.1;q34.3) inherited from a mother with tics. Mate-pair sequencing revealed that the translocation breakpoints truncated the olfactomedin 1 ( OLFM1 ) gene and two uncharacterized transcripts. Reverse-transcription PCR identified several fusion transcripts in the carriers, and OLFM1 expression was found to be high in GTS-related human brain regions. As OLFM1 plays a role in neuronal development it is a likely candidate gene for neuropsychiatric disorders and haploinsufficiency of OLFM1 could be a contributing risk factor to the phenotype of the carriers. In addition, one of the fusion transcripts may exert a dominant-negative or gain-of-function effect. OLFM1 is unlikely to be a major GTS susceptibility gene as no point mutations or copy number variants affecting OLFM1 were identified in 175 additional patients. The translocation described is thus a unique event, but further studies in larger cohorts are required to elucidate involvement of OLFM1 in GTS pathogenesis.

The pericentric inv(10)(p11.2q21.2) mutation has been frequently identified in cytogenetic laboratories, is phenotypically silent, and is considered to be a polymorphic variant. Cloning and sequencing of the junction fragments on 10p11 and 10q21 revealed that neither inversion breakpoint directly involved any genes or repetitive sequences, although both breakpoint regions contain a number of repeats. All 20 apparently unrelated inv(10) families in our study had identical breakpoints, and detailed haplotype analysis showed that the inversions were identical by descent. Thus, although considered a common variant, inv(10)(p11.2q21.2) has a single ancestral founder among northern Europeans.

The clinical, morphologic, and cytogenetic features of two hematologic malignancies--one acute myeloid leukemia with minimal differentiation (AML-MO) and one therapy-related myelodysplastic syndrome (MDS)--with unbalanced translocations between 1q and 5q are reported. The translocations resulted in loss of 5q material in both cases and gain of 1q in the MDS. A compilation of previously published hematologic malignancies with translocations involving the long arms of chromosomes 1 and 5 revealed a total of 23 cases--11 with unbalanced and 12 with balanced t(1;5)--with the following morphologies: 11 AML, three MDS, two Philadelphia-positive chronic myeloid leukemias, three chronic myeloproliferative disorders, three acute lymphoblastic leukemias, and one chronic lymphocytic leukemia. Four patients had received chemotherapy including alkylating agents for a previous malignancy and one had been exposed to thorotrast. Among the 14 patients for whom survival data exist, all except three have died. The t(1;5) was found as the sole abnormality in six cases, whereas it was apparently secondary--occurring in a subclone or together with the well-known primary abnormalities t(8;21), t(9;22), and t(15;17)--in nine cases. The breakpoints in 1q varied from 1q11 to 1q43, with a clustering to 1q21-23, and the 5q breaks occurred in 5q11 to 5q35, mainly in the distal 5q3 region. The unbalanced 1;5 translocations resulted in gain of 1q material in eight of the 11 cases, 1q21-1qter being duplicated in four of them, and in loss of 5q, most often the 5q3 region, in 10 of the neoplasms. We conclude that translocations between 1q and 5q, although cytogenetically heterogeneous, are associated with hematologic malignancies of the myeloid lineages and with previous mutagenic exposure, and that t(1;5) seems to confer a poor prognosis.

of >4000 reported duplications in an effort to refine our reporting criteria for duplications. Our results suggest limited diagnostic utility for reporting duplications less than 1Mb that do not involve known triplosensitive genes. In addition, duplications are also evaluated for involvement of known haploinsufficient genes at the breakpoints, with concern for potential gene disruption. At least one recent study suggests that the majority of these duplication breakpoints represent nondisruptive/benign events. To further support this observation, we characterized four recurrent partial-gene duplications using wholegenome mate pair sequencing to refine the breakpoints and assess the orientation of the duplicated genomic material in order to assist in the assignment of pathogenicity. We found that our data support the conclusion made by others that the majority of partial gene duplication breakpoints are non-disruptive in nature. Considerations for adoption of revised postnatal reporting criteria for duplications and overall interpretive strategies for duplication CNVs will be discussed.

This report describes the localization of the human gene for Oct-binding factor (OBF1), a B-cell-specific coactivator of octamer-binding transcription factors 1 and 2, to human chromosome 11q23.1 using somatic cell hybridization and fluorescence in situ hybridization. It also discusses the possible implications of the chromosomal location of this gene in certain hereditary malignancies. 12 refs., 1 fig.