These results demonstrate the utility of SNP genotyping data for detection of clinically significant abnormalities, including chimerism/mosaicism and recessive Mendelian disorders associated with autozygosity. The incidence of clinically significant low level mosaicism inferred from these cases suggests that this has hitherto been underestimated and chromosome mosaicism frequently occurs in the absence of indicative clinical features. The growing appreciation among clinicians and demand for SNP genotyping data poses significant challenges for the interpretation of LCSH, especially where there is no detailed phenotypic description to direct laboratory analysis. Finally, reporting of unexpected or hidden consanguinity revealed by SNP array analysis raises potential ethical and legal issues.

Objective Several studies have already shown the superiority of chromosomal microarray analysis (CMA) compared with conventional karyotyping for prenatal investigation of fetal ultrasound abnormality. This study used very high‐resolution single nucleotide polymorphism (SNP) arrays to determine the impact on detection rates of all clinical categories of copy number variations (CNVs), and address the issue of interpreting and communicating findings of uncertain or unknown clinical significance, which are to be expected at higher frequency when using very high‐resolution CMA. Design Prospective validation study. Setting Tertiary clinical genetics centre. Population Women referred for further investigation of fetal ultrasound anomaly. Methods We prospectively tested 104 prenatal samples using both conventional karyotyping and high‐resolution arrays. Main outcome measures The detection rates for each clinical category of CNV. Results Unequivocal pathogenic CNVs were found in six cases, including one with uniparental disomy (paternal UPD 14). A further four cases had a ‘likely pathogenic’ finding. Overall, CMA improved the detection of ‘pathogenic’ and ‘likely pathogenic’ abnormalities from 2.9% (3/104) to 9.6% (10/104). CNVs of ‘unknown’ clinical significance that presented interpretational difficulties beyond results from parental investigations were detected in 6.7% (7/104) of samples. Conclusions Increased detection sensitivity appears to be the main benefit of high‐resolution CMA. Despite this, in this cohort there was no significant benefit in terms of improving detection of small pathogenic CNVs. A potential disadvantage is the high detection rate of CNVs of ‘unknown’ clinical significance. These findings emphasise the importance of establishing an evidence‐based policy for the interpretation and reporting of CNVs, and the need to provide appropriate pre‐ and post‐test counselling.

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.