title: The Diagnostic Utility of Single Long Contiguous Stretches of Homozygosity in Patients without Parental Consanguinity.
abstract: We present data from our clinical department's experience with chromosomal microarray analysis (CMA) regarding the diagnostic utility of 1 or 2 long contiguous stretches of homozygosity (LCSHs) in an outbred population. The study group consisted of 2,110 consecutive patients from 2011 to 2014 for whom CMA was performed. The minimum cut-off size for defining a homozygous stretch was 5 Mb. To focus on cases with no parental consanguinity, we further studied only patients in whom the total length of homozygous stretches did not exceed 28 Mb or 1% of the autosomal genome length. We identified 6 chromosomal regions where homozygous stretches appeared in at least 3 patients and excluded these from further analysis. In 2 out of 120 patients with an isolated finding of 1 or 2 non-recurrent LCSHs, a plausible candidate gene associated with their phenotype was identified within the homozygous stretch. In both of these cases, a pathogenic mutation was detected, leading to diagnoses of pyruvate kinase deficiency and Marinesco-Sjögren syndrome. To clarify whether previously found homozygous stretches could be important for the interpretation of genome-wide sequencing data, we report 7 cases in which homozygous stretches not encompassing a clinically associated gene were first found on CMA, followed by the diagnostic whole-exome sequencing. The diagnostic utility of single LCSHs, unlikely to be caused by uniparental disomy, is discussed in detail.
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Biomedicine, Institute of Biomedicine and Translational Medicine, Tartu, Estonia.
authors.forename: Sander
authors.initials: S
authors.lastname: Pajusalu
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Institute of Molecular and Cell Biology, Tartu, Estonia.
authors.forename: Olga
authors.initials: O
authors.lastname: Žilina
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Pediatrics, University of Tartu, Tartu, Estonia.
authors.forename: Maria
authors.initials: M
authors.lastname: Yakoreva
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
authors.forename: Pille
authors.initials: P
authors.lastname: Tammur
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
authors.forename: Kati
authors.initials: K
authors.lastname: Kuuse
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
authors.forename: Triin
authors.initials: T
authors.lastname: Mölter-Väär
authors.affiliation: Institute of Molecular and Cell Biology, Tartu, Estonia; Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Margit
authors.initials: M
authors.lastname: Nõukas
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Biomedicine, Institute of Biomedicine and Translational Medicine, Tartu, Estonia; Department of Pediatrics, University of Tartu, Tartu, Estonia.
authors.forename: Tiia
authors.initials: T
authors.lastname: Reimand
authors.affiliation: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Pediatrics, University of Tartu, Tartu, Estonia.
authors.forename: Katrin
authors.initials: K
authors.lastname: Õunap
keywords: Autosomal recessive disease; Chromosomal microarray analysis; Clinical diagnostics; Long contiguous stretches of homozygosity; Variants of unclear clinical significance; Whole-exome sequencing