The utility of runs of homozygosity in the identification of pathogenic variants in individuals with rare diseases
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Runs of homozygosity (ROH) provide important clues regarding uniparental disomy (UPD), homozygosity for recessive variants and parental consanguinity. In this retrospective study, we have evaluated the utility of ROH in identifying the genetic causes of rare diseases.
Methods:
A total of 2787 unrelated patients who underwent CMA testing and publicly available SNP microarray data from 3488 unrelated individuals in the general population were included in this study. Electronic medical records of 233 patients with non-recurrent ROH were reviewed to obtain information on follow-up genetic testing to identify the genetic causes.
Results:
Nine hundred forty-seven patients had at least one ROH >5 Mb and the vast majority of these ROH (75%) were recurrent. Of the seven recurrent overlapping ROH with >1% frequency, ROH at 16p11.2p11.1 was significantly increased in our patient population compared to general population, particularly in the Hispanic/Latino and Native Americans. About 1% (26/2787) of patients had possible UPD, including one each involving imprinting disorder loci on chromosomes 6, 7, 11 and 14. Follow-up testing on two patients revealed paternal UPD(14) in one patient and possible paternal UPD(6) in the other. Seventy-eight of 233 patients with non-recurrent ROH underwent follow-up sequencing-based studies, which showed deleterious homozygous variants in 13 patients and homozygous variants of uncertain significance in six patients. Reclassification of variants of uncertain significance in all six patients resulted in a likely pathogenic classification for one patient with congenital heart defect. This patient had homozygous likely pathogenic loss of function variant in TMEM260 besides homozygous missense variants in five other genes that were not reported to be associated with congenital heart defect. In seven of the 14 patients with deleterious homozygous variants, the causal genes were found to be within ROH > 5 Mb. The causal genes were within ROH range in size from 1.5 to 4.3 Mb in another five patients, of which four were Native Americans. Causal genes in the remaining two patients were not located within the ROH of 1 Mb and larger. Of the 14 patients, five were Native Americans, including two carrying a deleterious variant associated with HOXA1 deficiency, known to be more prevalent in Southwestern Athabaskans. Additional studies are needed to determine if the deleterious variants found in the remaining three Native American patients represent common diseases-causing variants in this population.
Conclusion:
These findings highlight the importance of investigating ROH 1Mb and larger for deleterious homozygous variants via sequencing studies in patients with normal CMA results.
Runs of homozygosity (ROH) provide important clues regarding uniparental disomy (UPD), homozygosity for recessive variants and parental consanguinity. In this retrospective study, we have evaluated the utility of ROH in identifying the genetic causes of rare diseases.
Methods:
A total of 2787 unrelated patients who underwent CMA testing and publicly available SNP microarray data from 3488 unrelated individuals in the general population were included in this study. Electronic medical records of 233 patients with non-recurrent ROH were reviewed to obtain information on follow-up genetic testing to identify the genetic causes.
Results:
Nine hundred forty-seven patients had at least one ROH >5 Mb and the vast majority of these ROH (75%) were recurrent. Of the seven recurrent overlapping ROH with >1% frequency, ROH at 16p11.2p11.1 was significantly increased in our patient population compared to general population, particularly in the Hispanic/Latino and Native Americans. About 1% (26/2787) of patients had possible UPD, including one each involving imprinting disorder loci on chromosomes 6, 7, 11 and 14. Follow-up testing on two patients revealed paternal UPD(14) in one patient and possible paternal UPD(6) in the other. Seventy-eight of 233 patients with non-recurrent ROH underwent follow-up sequencing-based studies, which showed deleterious homozygous variants in 13 patients and homozygous variants of uncertain significance in six patients. Reclassification of variants of uncertain significance in all six patients resulted in a likely pathogenic classification for one patient with congenital heart defect. This patient had homozygous likely pathogenic loss of function variant in TMEM260 besides homozygous missense variants in five other genes that were not reported to be associated with congenital heart defect. In seven of the 14 patients with deleterious homozygous variants, the causal genes were found to be within ROH > 5 Mb. The causal genes were within ROH range in size from 1.5 to 4.3 Mb in another five patients, of which four were Native Americans. Causal genes in the remaining two patients were not located within the ROH of 1 Mb and larger. Of the 14 patients, five were Native Americans, including two carrying a deleterious variant associated with HOXA1 deficiency, known to be more prevalent in Southwestern Athabaskans. Additional studies are needed to determine if the deleterious variants found in the remaining three Native American patients represent common diseases-causing variants in this population.
Conclusion:
These findings highlight the importance of investigating ROH 1Mb and larger for deleterious homozygous variants via sequencing studies in patients with normal CMA results.
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