title: Rapid and robust screening of the Menkes disease/occipital horn syndrome gene.
abstract: Menkes disease and occipital horn syndrome (OHS) are allelic neurogenetic disorders of copper transport associated with mutations in an X-linked gene, ATP7A. This gene encodes a copper-transporting P-type ATPase. The spectrum of mutations at the Menkes/OHS locus is estimated to include 1% chromosomal rearrangements and 15-20% large deletions, with the remaining defects involving small alterations. There is a compelling need for a rapid and reliable molecular diagnostic approach for patients and families impacted by these conditions. In addition to testing suspected affected males, carrier screening of females in Menkes/OHS families and prenatal evaluation of at-risk pregnancies will be enhanced by the wider availability of robust mutation analysis for this large (23-exon) locus. Here we describe a stepwise approach to mutation screening for these disorders that successfully identified molecular alterations in over 95% of our patient population (n = 49). This genomic DNA-based technique employs multiplex PCR, heteroduplex analysis, and direct sequencing, in a serial fashion. This approach should find application in molecular diagnostic laboratories in the United States and other countries. Currently, only a single European center provides commercial testing for unknown mutations in Menkes/OHS patients, even though these disorders occur worldwide.
authors.affiliation: Unit on Pediatric Genetics, Laboratory of Clinical Genomics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Po-Ching
authors.initials: PC
authors.lastname: Liu
authors.forename: Patricia E
authors.initials: PE
authors.lastname: McAndrew
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000175:diagnosis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins; D017384:Sequence Deletion
chemical_list: D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases