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

• Published in: Journal of medical genetics Vol. 47; no. 11; pp. 786 - 790
• Main Authors: Staropoli, John F, Xin, Winnie, Sims, Katherine B
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.11.2010; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Age; Base Sequence; Biological and medical sciences; Blindness - congenital; Blindness - genetics; Child; Chromosome Deletion; Chromosomes; Chromosomes, Human, X - genetics; clinical genetics; contiguous gene deletion syndrome; Cytomegalovirus; DNA Mutational Analysis; Dyspnea; Eye Proteins - genetics; Family Health; Fatal Outcome; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Diseases, X-Linked; Genetics of eukaryotes. Biological and molecular evolution; Genomes; genomic rearrangement; Hearing loss; Humans; Hypertension, Pulmonary - genetics; idiopathic pulmonary hypertension; Infant; Male; Malformations of the eye; Medical genetics; Medical sciences; Molecular and cellular biology; molecular genetics; monoamine oxidase; Mutation; Nerve Tissue Proteins - genetics; Nervous System Diseases - genetics; neurology; Norrie disease; Ophthalmology; Pedigree; Pneumonia; Pulmonary arteries; Pulmonary hypertension; Spasms, Infantile - genetics; United States > US; California; Human; Microdeletion; Nervous system diseases; Norrie disease; Retinopathy; Respiratory disease; Family study; Segregation; Idiopathic; Cardiovascular disease; Pulmonary hypertension; Genetic disease; Segregation analysis; Eye disease; ENT disease; Genetics
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmg.2010.079301

IntroductionNorrie 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 ResultsMolecular 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.