The Diagnostic Utility of Single Long Contiguous Stretches of Homozygosity in Patients without Parental Consanguinity

Molecular Syndromology

Triin Mölter-Väär¹  Tiia Reimand¹  Olga Žilina¹  Maria Yakoreva¹  Pille Tammur¹  Kati Kuuse¹  Katrin Õunap¹  Margit Nõukas¹  Sander Pajusalu¹ 

[1] aDepartment of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia

关键词: Autosomal recessive disease;    Chromosomal microarray analysis;    Clinical diagnostics;    Long contiguous stretches of homozygosity;    Variants of unclear clinical significance;    Whole-exome sequencing;   

DOI  :  10.1159/000438776

学科分类：基础医学

来源: S Karger AG

【 摘 要 】

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.

【 授权许可】

Unknown