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Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.4
  1. John F Staropoli1,2,
  2. Winnie Xin2,3,
  3. Katherine B Sims2,3
  1. 1Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2Neurogenetics DNA Diagnostic Laboratory, Massachusetts General Hospital, Center for Human Genetic Research, Boston, Massachusetts, USA
  3. 3Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Katherine B Sims, MGH Neurogenetics DNA Diagnostic Laboratory, Simches Research Building, 5-300, 185 Cambridge Street, Room 5238, Boston, MA 02114, USA; ksims{at}


Introduction Norrie disease is a rare X-linked congenital retinal vasculopathy that may be accompanied by sensorineural deafness, mental retardation, and other neurological deficits. Here we present a family in which Norrie disease co-segregated with either early-onset idiopathic pulmonary hypertension or sudden death preceded by a period of progressive dyspnea. Neither Norrie disease, nor its atypical variants described to date, have been associated with this extended clinical phenotype.

Methods and Results Molecular analysis of the Norrie disease gene (NDP) and adjacent loci was performed by multiplex ligation-dependent probe amplification and comparative genomic hybridisation. Affected males in this family showed an inherited hemizygous deletion restricted to NDP and two immediately telomeric genes, monoamine oxidase-B (MAO-B) and monoamine oxidase-A (MAO-A), which encode closely related enzymes that metabolize biogenic amines including serotonin, dopamine, and norepinephrine. Sequencing of the deletion junction showed an unusual pattern in which a region of microhomology flanked intervening genomic sequence.

Conclusion Because abnormalities of biogenic amines, particularly serotonin, have been implicated in the pathophysiology of pulmonary hypertension, we propose that presumed MAO deficiency in these patients may represent a novel risk factor for pulmonary hypertension, particularly forms with very early onset. Fine-mapping of other microdeletions at this locus may provide insights into additional mechanisms for nonrecurrent genomic rearrangements at this and other chromosomal loci.

  • Norrie disease
  • idiopathic pulmonary hypertension
  • genomic rearrangement
  • monoamine oxidase
  • contiguous gene deletion syndrome
  • clinical genetics
  • molecular genetics
  • neurology
  • pulmonary hypertension
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  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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