Hum Genet (1999) 104:56–63 © Springer-Verlag 1999 Abstract Börjeson-Forssman-Lehmann syndrome (BFLS) is a syndromal X-linked mental retardation, which maps by linkage to the q26 region of the human X chromosome. We have identified a male patient with BFLS-like features and a duplication, 46,Y,dup(X)(q26q28), inherited from his phenotypically normal mother. Fluorescence in situ hybridisation using yeast artificial chromosome clones from Xq26 localised the duplication breakpoint to an ~400- kb interval in the Xq26.3 region between DXS155 and DXS294/DXS730. Database searches and analysis of avail- able genomic DNA sequence from the region revealed the presence of the fibroblast growth factor homologous factor gene, FHF2, within the duplication breakpoint interval. The gene structure of FHF2 was determined and two new exons were identified, including a new 5′ end exon, 1B. FHF2 is a large gene extending over ~200 kb in Xq26.3 and is composed of at least seven exons. It shows tissue-specif- ic alternative splicing and alternative transcription starts. Northern blot hybridisation showed highest expression in brain and skeletal muscle. The FHF2 gene localisation and tissue-specific expression pattern suggest it to be a candi- date gene for familial cases of the BFLS syndrome and oth- er syndromal and non-specific forms of X-linked mental re- tardation mapping to the region. J. Gecz ( ✉ ) · E. Baker · A. Donnelly · G. R. Sutherland J. C. Mulley Centre for Medical Genetics, Department of Cytogenetics and Molecular Genetics, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia e-mail: jgecz@mad.adelaide.edu.au, Tel.: +61-8-8204-7023, Fax: +61-8-8204-7342 J. Gecz · G. R. Sutherland Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia A. Donnelly · J. C. Mulley Department of Genetics, University of Adelaide, Adelaide, SA, Australia J. E. Ming · D. M. McDonald-McGinn · N. B. Spinner · E. H. Zackai Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pa., USA ORIGINAL INVESTIGATION Jozef Gecz · Elizabeth Baker · Andrew Donnelly Jeffrey E. Ming · Donna M. McDonald-McGinn Nancy B. Spinner · Elaine H. Zackai Grant R. Sutherland · John C. Mulley Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Börjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient Received: 18 June 1998 / Accepted: 22 September 1998 Introduction Börjeson-Forssman-Lehmann syndrome (BFLS; MIM 301900) is an X-linked mental retardation characterised by moderate-to-severe mental deficiency, hypogonadism, hy- pometabolism and marked obesity, short stature and char- acteristic facial and skeletal anomalies (Börjeson et al. 1962). BFLS is one of more than 147 clinically delineated X-linked mental retardation syndromes (XLMRs) mapped to the human X chromosome (Lubs et al. 1996). Although the initial report on the BFLS syndrome by Börjeson et al. (1962) suggested X-linked inheritance, this was not confirmed until more than two decades later when the BFLS gene was mapped in two large BFLS pedigrees. Mathews et al. (1989) and Turner et al. (1989) reported linkage to markers from the Xq26–q27 region on two mild- ly affected BFLS families. In the family of Mathews et al. (1989), the highest lod scores were 2.32 with DXS10 and 2.24 with DXS51, both at θ=0.0. The family of Turner et al. (1989) showed the highest lod score, 2.1 with DXS51, at θ=0.0. Gedeon et al. (1996a) refined the localisation of the BFLS in the family of Turner et al. (1989) by collecting ad- ditional family members and testing new genetic markers from the Xq26–q27 region. The maximum two-point lod score reached 2.61 with DXS294 at a recombination frac- tion of zero. The data were consistent with the placement of the BFLS gene in this family between the DXS425 and DXS105 markers on the background genetic map, or an in- terval of 24.6 cM (Gedeon et al. 1996a). Gedeon et al. (1996a) tested the HMG-box region of the SOX3 gene, which was a positional candidate for BFLS; no mutations were detected.