J Med Genet 42:666-672 doi:10.1136/jmg.2004.026989
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Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1

  1. HG Kim1,
  2. S R Herrick2,
  3. E Lemyre3,
  4. S Kishikawa1,
  5. J A Salisz4,
  6. S Seminara5,
  7. M E MacDonald1,
  8. G A P Bruns6,
  9. C C Morton7,
  10. B J Quade2,
  11. J F Gusella1
  1. 1Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital/Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
  2. 2Department of Pathology, Brigham and Women’s Hospital/Harvard Medical School
  3. 3Medical Genetics Service, Hôpital Ste Justine, University of Montreal, Montreal, Canada
  4. 4West Shore Urology, Mercy Drive, Muskegon, Michigan, USA
  5. 5Reproductive Endocrine Unit, Massachusetts General Hospital
  6. 6Genetics Division, Children’s Hospital/Department of Pediatrics, Harvard Medical School
  7. 7Departments of Obstetrics, Gynecology and Reproductive Biology and Pathology, Brigham and Women’s Hospital/Harvard Medical School
  1. Correspondence to:
 Dr James F Gusella
 Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital/Department of Genetics, Harvard Medical School, CNY149-6214, 13th Street, Boston, Massachusetts 02129, USA;

    We have established the Developmental Genome Anatomy Project (DGAP; // to take advantage of the unique opportunity to locate genes of developmental importance provided by apparently balanced chromosomal rearrangements associated with phenotypic abnormalities. By positional cloning at or near the breakpoints, we aim to identify the crucial disease genes whose functions have been disrupted by rearrangement.1 Kallmann’s syndrome (KS) is a developmental disorder characterised by anosmia resulting from agenesis of the olfactory lobes and hypogonadism secondary to deficiency of hypothalamic gonadotropin releasing hormone (GnRH). Its prevalence has been estimated at 1/10 000 in males and 1/50 000 in females. In a minority of cases there are inactivating mutations of KAL1, an X linked gene encoding a putative adhesion molecule thought to mediate embryonic neuronal migration.2,3 Constitutional autosomal chromosome translocations associated with KS have been reported, but the disrupted genes have not been identified.4–6

    We have studied a white male subject with a de novo balanced translocation between chromosomes 7, in band p12.3, and 8, in band p11.2 (fig 1A), who was diagnosed on clinical examination to have hypogonadotropic hypogonadism (infantile testes), azoospermia, and cleft lip and palate, without frank anosmia. As a KS patient with a microdeletion involving the same 8p11.2 region had been reported, we sought to identify the chromosome 8 gene disrupted in this reciprocal translocation as a likely candidate for the cause of autosomal KS as well as of isolated hypogonadotropic hypogonadism.7 While this breakpoint in FGFR1 was being characterised, Dodé et al identified FGFR1 mutations in several patients, establishing that disruption of FGFR1 can cause autosomal dominant KS.8

    Figure 1

     Fluorescent in situ hybridisation (FISH) mapping of the chromosome 8 breakpoint. (A) Ideogram illustrating the balanced t(7;8)(p12.3;p11.2) in the patient. (B) FISH mapping with RP11-100B16, labelled with SpectrumOrange, resulted in hybridisation …