Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

RD–Connect Genome-Phenome Analysis Platform and URD-Cat Data Contributors

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)–Connect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines.

Original languageEnglish (US)
Pages (from-to)1205-1215
Number of pages11
JournalJournal of Molecular Diagnostics
Issue number9
StatePublished - Sep 2020

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Medicine


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