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.

Large gene panel sequencing in clinical diagnostics—results from 501 consecutive cases

“…Thus, some de novo mutations could have been misinterpreted as VUSs in initial analysis due to lack of parental genetic information. Regarding autosomal recessive disorders, causative compound heterozygous mutations appeared more often than did homozygous mutations, which is consistent with WES‐based studies of outbred populations, as well as our previous study showing that homozygous stretches detected by CMA are rarely associated with genetic disorders in Estonia …”

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

“…And that seems to be the approach of groups which analyze larger samples. The LCSH that are found recurrently in patients and unaffected parents are considered common variation and ignored from a certain point on [ 13 , 25 – 28 ]. 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 now report them to contribute with the growing evidence.…”

“…This percentage was chosen because the frequency of ≥1%, which is the usual threshold to define common polymorphisms of SNPs in a population, was not considered applicable here because this is an affected cohort. Also others have chosen the same threshold (or lower) to consider LCSH found in a affected cohort as common variation, essentially without clinical significance for their analysis [ 13 , 25 – 28 ]. Hence, in doing so we believe to have an adequate safety margin for selecting common LCSH due to ancestral haplotypes rather than due to consanguinity or other pathogenesis-related mechanisms.…”

“…There is no work about the common LCSH which segregate in the south Brazilian population, because of the high cost of SNP arrays or CMA platforms that incorporate SNP detection, therefore population-based SNP array studies are unlikely to be performed in Brazil anytime soon. In clinical setting others have registered LCSH that were considered, with some caution, as common variation, not clinically relevant to the mainly neurodevelopmental diseases being investigated, because of their high frequency (up from about 3–5%) in the samples, some of which included non-affected parents [ 13 , 25 – 28 ]. However, it is probable that those variations are population-specific and will vary accordingly.…”

Ultrasound findings provide clues to investigate founder mutations expressed as runs of homozygosity in chromosomal microarray studies

“…Various human populations became isolated either by particular geographical conditions, or owing to social or religious constraints. Because of this isolation, some genetic diseases became relatively frequent in these populations due to a founder effect and genetic drift …”