Microarray testing in clinical diagnosis: an analysis of 5,300 New Zealand patients.

BACKGROUND: The use of Microarray (array CGH) analysis has become a widely accepted front-line test replacing G banded chromosome studies for patients with an unexplained phenotype. We detail our findings of over 5300 cases. RESULTS: Of 5369 pre and postnatal samples, copy number variants (CNVs) were detected in 28.3 %, of which ~40 % were deletions and ~60 % were duplications. 96.8 % of cases with a CNV <5 Mb would not have been detected by G banding. At least 4.9 % were determined to meet the minimum criteria for a known syndrome. Chromosome 17 provided the greatest proportion of pathogenic CNVs with 65 % classified as (likely) pathogenic. X chromosome CNVs were the most commonly detected accounting for 4.2 % of cases, 0.7 % of these being classified as cryptic (likely) pathogenic CNVs. CONCLUSIONS: Microarray analysis as a primary testing strategy has led to a significant increase in the detection of CNVs (~29 % overall), with ~9 % carrying pathogenic CNVs and one syndromic case identified per 20 referred patients. We suggest these frequencies are consistent with other heterogeneous studies. Conversely, (likely) pathogenic X chromosome CNVs appear to be greater compared with previous studies.

SNP Analysis and Whole Exome Sequencing: Their Application in the Analysis of a Consanguineous Pedigree Segregating Ataxia.

Autosomal recessive cerebellar ataxia encompasses a large and heterogeneous group of neurodegenerative disorders. We employed single nucleotide polymorphism (SNP) analysis and whole exome sequencing to investigate a consanguineous Maori pedigree segregating ataxia. We identified a novel mutation in exon 10 of the SACS gene: c.7962T>G p.(Tyr2654*), establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Our findings expand both the genetic and phenotypic spectrum of this rare disorder, and highlight the value of high-density SNP analysis and whole exome sequencing as powerful and cost-effective tools in the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

Developmental delay referrals and the roles of Fragile X testing and molecular karyotyping: a New Zealand perspective.

Global developmental delay (GDD) affects ~1-3% of children, many of whom will also have intellectual disability (ID). Fragile X is the major genetic cause of GDD with mental retardation (MR) in males, accounting for ~20% of all X-linked MR. As Fragile X has serious genetic implications, the overwhelming majority of developmental delay (DD) cases referred to our laboratory are concerned with the exclusion of a diagnosis of Fragile X, along with simultaneous karyotype analysis to confirm chromosome aberrations. Critically, molecular laboratories have generally experienced a falling positive detection frequency of Fragile X. In this context, the recent implementation of array­based techno-logy has significantly increased the likelihood of detecting chromosome aberrations that underpin DD. In the current study, we report a Fragile X mutation detection frequency for DD referrals that is comparable with the falling UK detection frequencies. In addition, we find that there is a 9­fold greater likelihood of detecting clinically significant chromosomal aberrations than of detecting a full Fragile X mental retardation 1 (FMR1) gene CGG repeat expansion in cases referred on the basis of DD. We propose a more efficent sequential testing algorithm that involves an initial molecular karyotype, cascading to FMR1 gene analysis in the event of a negative result.