title: Extending the scope of diagnostic chromosome analysis: detection of single gene defects using high-resolution SNP microarrays.
abstract: Microarray analysis has provided significant advances in the diagnosis of conditions resulting from submicroscopic chromosome abnormalities. It has been recommended that array testing should be a "first tier" test in the evaluation of individuals with intellectual disability, developmental delay, congenital anomalies, and autism. The availability of arrays with increasingly high probe coverage and resolution has increased the detection of decreasingly small copy number changes (CNCs) down to the intragenic or even exon level. Importantly, arrays that genotype SNPs also detect extended regions of homozygosity. We describe 14 examples of single gene disorders caused by intragenic changes from a consecutive set of 6,500 tests using high-resolution SNP microarrays. These cases illustrate the increased scope of cytogenetic testing beyond dominant chromosome rearrangements that typically contain many genes. Nine of the cases confirmed the clinical diagnosis, that is, followed a "phenotype to genotype" approach. Five were diagnosed by the laboratory analysis in the absence of a specific clinical diagnosis, that is, followed a "genotype to phenotype" approach. Two were clinically significant, incidental findings. The importance of astute clinical assessment and laboratory-clinician consultation is emphasized to optimize the value of microarrays in the diagnosis of disorders caused by single gene copy number and sequence mutations.
authors.affiliation: VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
authors.forename: Damien L
authors.initials: DL
authors.lastname: Bruno
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.forename: Trent
authors.initials: T
authors.lastname: Burgess
authors.forename: Kathy
authors.initials: K
authors.lastname: Butler
authors.forename: Sylvea
authors.initials: S
authors.lastname: Corrie
authors.forename: David
authors.initials: D
authors.lastname: Francis
authors.forename: Devika
authors.initials: D
authors.lastname: Ganesamoorthy
authors.forename: Louise
authors.initials: L
authors.lastname: Hills
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.forename: Darren
authors.initials: D
authors.lastname: O'Rielly
authors.forename: Ralph
authors.initials: R
authors.lastname: Oertel
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Prabhakara
authors.forename: Nicholas
authors.initials: N
authors.lastname: Salce
authors.forename: Howard R
authors.initials: HR
authors.lastname: Slater
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D005799:Genes, Dominant; D005808:Genes, Recessive; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy