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. 2019 Mar 12;12(1):50.
doi: 10.1186/s12920-019-0496-5.

Long contiguous stretches of homozygosity detected by chromosomal microarrays (CMA) in patients with neurodevelopmental disorders in the South of Brazil

Tiago Fernando Chaves  1 , Luan Freitas Oliveira  2 , Maristela Ocampos  3 , Ingrid Tremel Barbato  4 , Gisele Rozone de Luca  5 , Jorge Humbeto Barbato Filho  6 , Louise Lapagesse de Camargo Pinto  7 , Pricila Bernardi  8 , Angelica Francesca Maris  9
Affiliations

Long contiguous stretches of homozygosity detected by chromosomal microarrays (CMA) in patients with neurodevelopmental disorders in the South of Brazil

Tiago Fernando Chaves et al. BMC Med Genomics. .

Abstract

Background: Currently, 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.

Methods: In 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.

Results: In 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%).

Conclusions: In this work, we show the importance and usefulness of interpreting LCSH in the results of CMA wich incorporate SNPs.

Keywords: Autism; Developmental disorders; Homozygosity; Intellectual disability; LCSH; Microarrays; ROH; SNPs.

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Conflict of interest statement

Ethics approval and consent to participate

The project was submitted and approved by the Research Ethics Committee of the Hospital Infantil Joana de Gusmão, the children hospital of Florianópolis-SC, Brazil, under the Nr 2,339,104, and respects the guidelines and criteria established by the resolution 466/12 of the Brazilian National Health Council. Patients or their caregivers signed the Informed Consent Form to participate in the study. In cases in which it was not possible to contact the patient for any justifiable reason (loss of contact information, mainly) the data was used and a Justification of Absence of Consent was signed by the research team, ensuring the commitment to maintain confidentiality and privacy of the individuals whose data and/or information was collected in the records.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flowchart of the analyses. Legend Fig. 1 - Flowchart depicting the steps of analyses of the exams that presented LCSHs, based on their size and distribution in the genomes of the individual
Fig. 2
Fig. 2
Chromosomal distribution of the 11 cases with LCSH (single or sum) ≥10 Mbp restricted to one chromosome, suggesting putative UPDs
Fig. 3
Fig. 3
Regions of LCSH considered common (frequency ≥ 5%) identified among 430 CMA results of a cohort with developmental disorders
See this image and copyright information in PMC

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