Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.4.
BACKGROUND
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.


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.


CONCLUSIONS
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.
Staropoli
John F
JF
MGH Neurogenetics DNA Diagnostic Laboratory, Simches Research Building 5-300, 185 Cambridge Street, Room 5238, Boston, MA 02114, USA.
Xin
Winnie
W
Sims
Katherine B
KB
D001483:Base Sequence; D001766:Blindness / Q000151:congenital / Q000235:genetics; D002648:Child; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D040181:Genetic Diseases, X-Linked; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D007223:Infant; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009422:Nervous System Diseases / Q000235:genetics; D010375:Pedigree; D012162:Retinal Degeneration; D013036:Spasms, Infantile / Q000235:genetics
D005136:Eye Proteins; C081848:NDP protein, human; D009419:Nerve Tissue Proteins