Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps approximately 900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter-->4p15.1::17q25.1-->17qter;7qter-->7p15.3::4p15.1-->4pter;8pter-->8q12.1::7p15.3-->7pter;17pter-->17q25.1::8q12.1-->8qter). Surprisingly, the 17q breakpoint maps approximately 1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3' of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.

Wolf-Hirschhorn syndrome (WHS) and Patau syndrome are two of the most severe conditions resulting from chromosome abnormalities. WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13. Though the etiologies of these syndromes differ, they share several features including pre- and postnatal growth retardation, microcephaly, cleft lip and palate, and cardiac anomalies. We present here a female fetus with deletion of 4p16 → pter and duplication of 13q32 → qter due to unbalanced segregation of t(4;13)(p16;q32) in the father. She displayed overlapping features of both of these syndromes on ultrasound. To the best of our knowledge, this is the first report of a fetus with both partial trisomy 13 and deletion of 4p16, the critical region for WHS.

Goldenhar syndrome, also called hemifacial microsomia or oculo-auriculo-verterbal dysplasia (OAVS) (MIM 164210), is a birth defect involving the first and second branchial arch derivatives with an incidence of 1/5000. The variable phenotype includes mostly unilateral deformity of the external ear and small ipsilateral half of the face with epibulbar dermoid and vertebral anomalies. A genome-wide search in one family suggested linkage to a region of 10.7 cM on chromosome 14q32; however, no candidate genes have been identified. We report on a 9-month old with OAVS and a pericentric inversion of chromosome 14 which he inherited from his phenotypically normal mother. Fluorescence in-situ hybridization analysis with bacterial artificial chromosome clones from chromosome 14 showed the breakpoint on 14q maps distal to 14q21.2, thus confirming the cytogenetic breakpoints. In light of previous linkage studies mapping OAVS to 14q, we propose that the long arm breakpoint in our proband disrupted a potential candidate gene for OAVS resulting in his clinical phenotype.

Pallister-Killian syndrome (PKS), a rare disorder, is characterized by tissue-limited or tissue-specific mosaicism. The characteristic chromosome abnormality associated with PKS is i(12p), which is seen predominantly in skin fibroblast cultures. Diagnosis of i(12p) has been carried out on buccal smears before and was shown to be an easy and feasible method. All previously published studies used alpha-satellite probes for the diagnosis and as such have several pitfalls. Our approach, using dual-color, locus-specific probes, has high specificity and sensitivity for the diagnosis of i(12p). Using statistical analysis, we have also confirmed that the signal pattern in interphase nuclei is consistent with isochromosome 12p.

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