Clinical utility of exome sequencing in individuals with large homozygous regions detected by chromosomal microarray analysis.

Autor: Prasad A; Lineagen, Inc., 2677 East Parleys Way, Salt Lake City, UT, 84109, USA. aprasad@lineagen.com., Sdano MA; Department of Biochemistry, University of Utah, Salt Lake City, USA., Vanzo RJ; Lineagen, Inc., 2677 East Parleys Way, Salt Lake City, UT, 84109, USA., Mowery-Rushton PA; Lineagen, Inc., 2677 East Parleys Way, Salt Lake City, UT, 84109, USA., Serrano MA; Lineagen, Inc., 2677 East Parleys Way, Salt Lake City, UT, 84109, USA., Hensel CH; Lineagen, Inc., 2677 East Parleys Way, Salt Lake City, UT, 84109, USA., Wassman ER; Lineagen, Inc., 2677 East Parleys Way, Salt Lake City, UT, 84109, USA.
Jazyk: angličtina
Zdroj: BMC medical genetics [BMC Med Genet] 2018 Mar 20; Vol. 19 (1), pp. 46. Date of Electronic Publication: 2018 Mar 20.
DOI: 10.1186/s12881-018-0555-3
Abstrakt: Background: Chromosomal microarray analysis (CMA) is recommended as the first-tier clinical diagnostic test for individuals with developmental disabilities. In addition to detecting copy number variations, CMA platforms with single nucleotide polymorphism probes can detect large homozygous regions within the genome, which represent potential risk for recessively inherited disorders.
Methods: To determine the frequency in which pathogenic or likely pathogenic variants can be detected in these regions of homozygosity, we performed whole exome sequencing (WES) in 53 individuals where homozygosity was detected by CMA. These patients were referred to our clinical laboratory for a variety of neurodevelopmental conditions including autism spectrum disorder, developmental delay, epilepsy, intellectual disability and microcephaly.
Results: In 11.3% (6/53) of cases, the analysis of homozygous variants revealed pathogenic or likely pathogenic variants in GJB2, TPP1, SLC25A15, TYR, PCCB, and NDUFV2 which are implicated in a variety of diseases. The evaluation of heterozygous variants with autosomal dominant inheritance, compound heterozygotes and variants with X-linked inheritance revealed pathogenic or likely pathogenic variants in PNPLA4, CADM1, HBB, SOS1, SFTPC, OTC and ASMT in 15.1% (8/53) of cases. Two of these patients harbored both homozygous and heterozygous variants relevant to their phenotypes (TPP1 and OTC; GJB2 and ASMT).
Conclusions: Our study highlights the clinical utility of WES in individuals whose CMA uncovers homozygosity. Importantly, we show that when the phenotype is complex and homozygosity levels are high, WES can identify a significant number of relevant variants that explain neurodevelopmental phenotypes, and these mutations may lie outside of the regions of homozygosity, suggesting that the appropriate follow up test is WES rather than targeted sequencing.
Databáze: MEDLINE
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