Abstract
BackgroundCurrently, chromosomal microarrays (CMA) are recommended as first-tier test in the investigation of developmental disorders to examine copy number variations. The modern platforms also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH) also named runs of homozygosity (ROH). LCHS are chromosomal segments resulting from complete or segmental chromosomal homozygosity, which may be indicative of uniparental disomy (UPD), consanguinity, as well as replicative DNA repair events, however also are common findings in normal populations. Knowing common LCSH of a population, which probably represent ancestral haplotypes of low-recombination regions in the genome, facilitates the interpretation of LCSH found in patients, allowing to prioritize those with possible clinical significance. However, population records of ancestral haplotype derived LCSH by SNP arrays are still scarce, particularly for countries such as Brazil where even for the clinic, microarrays that include SNPs are difficult to request due to their high cost.MethodsIn this study, we evaluate the frequencies and implications of LCSH detected by Affymetrix CytoScan® HD or 750 K platforms in 430 patients with neurodevelopmental disorders in southern Brazil. LCSH were analyzed in the context of pathogenic significance and also explored to identify ancestral haplotype derived LCSH. The criteria for considering a region as LCSH was homozygosis ≥3 Mbp on an autosome.ResultsIn 95% of the patients, at least one LCSH was detected, a total of 1478 LCSH in 407 patients. In 2.6%, the findings were suggestive of UPD. For about 8.5% LCSH suggest offspring from first to fifth grade, more likely to have a clinical impact. Considering recurrent LCSH found at a frequency of 5% or more, we outline 11 regions as potentially representing ancestral haplotypes in our population. The region most involved with homozygosity was 16p11.2p11.1 (49%), followed by 1q21.2q21.3 (21%), 11p11.2p11.12 (19%), 3p21.31p21.2 (16%), 15q15 1q33p32.3 (12%), 2q11.1q12.1 (9%), 1p33p32.3 (6%), 20q11.21q11.23 (6%), 10q22.1q23.31 (5%), 6p22.2p22 (5%), and 7q11.22q11.23 (5%).ConclusionsIn this work, we show the importance and usefulness of interpreting LCSH in the results of CMA wich incorporate SNPs.
Highlights
Chromosomal microarrays (CMA) are recommended as first-tier test in the investigation of developmental disorders to examine copy number variations
Consanguinity The analysis of the long contiguous stretches of homozygosity (LCSH) distributed throughout several chromosomes indicated some degree of inbreeding in 26.5% of the cases, with over 18% suggesting kinship of seventh to sixth grade between the parents; 4.2%, fifth grade; 1.2%, fourth grade; 2%, third grade; 0.9%, second grade and in one case (0.2%) the kinship of the parents suggested incest, since it is a coefficient of inbreeding of first grade [father/ daughter, full siblings]
Following the same rationale and using similar criteria, LCSH ≥3 Mbp found in a frequency of 5% or higher, we identified 11 LCSH that were considered as common variation in our population and report them to contribute with the growing evidence
Summary
Chromosomal microarrays (CMA) are recommended as first-tier test in the investigation of developmental disorders to examine copy number variations. The modern platforms include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH) named runs of homozygosity (ROH). Long contiguous stretches of homozygosity (LCSH) can be detected by microarray platforms through probes specific for single nucleotide polymorphisms (SNPs) [1,2,3,4,5,6,7]. LCSH are observed throughout the human genome as consequence of endogamy or evolutionary forces [7] They are typical for inbred populations, LCSH are common and unexpectedly long in the genome of outbred populations [13], with continental distribution patterns, probably characterizing regions of low recombination in the genome [14]. The recombination-rate in the human genome is an average of roughly 2,5 recombinations per chromosomal pair, with the female meiosis showing more recombinations, 41.1 (95% CI: 39.9–42.4) than the paternal meiosis with 26.4 (95% CI, 25.7–27.2), and the telomere regions representing higher recombination rates [15]
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