Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.4. Issue 11 (2nd August 2010)

• Record Type: Journal Article
• Authors: Staropoli, John F; Xin, Winnie; Sims, Katherine B
• Is Part Of: Journal of medical genetics. Volume 47:Issue 11(2010)
• Page Start: 786
• Page End: 790
• Publication Date: 2010-08-02
• Subjects: Norrie disease -- idiopathic pulmonary hypertension -- genomic rearrangement -- monoamine oxidase -- contiguous gene deletion syndrome -- clinical genetics -- molecular genetics -- neurology -- pulmonary hypertension; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2010.079301
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.