Uniparental disomy screen of Irish rare disorder cohort unmasks homozygous variants of clinical significance in the TMCO1 and PRKRA genes

Abstract

A uniparental disomy (UPD) screen using whole genome sequencing (WGS) data from 164 trios with rare disorders in the Irish population was performed to identify large runs of homozygosity of uniparental origin that may harbour deleterious recessive variants. Three instances of whole chromosome uniparental isodisomy (UPiD) were identified: one case of maternal isodisomy of chromosome 1 and two cases of paternal isodisomy of chromosome 2. We identified deleterious homozygous variants on isodisomic chromosomes in two probands: a novel p (Glu59ValfsTer20) variant in TMCO1, and a p (Pro222Leu) variant in PRKRA, respectively. The overall prevalence of whole chromosome UPiD in our cohort was 1 in 55 births, compared to 1 in ∼7,500 births in the general population, suggesting a higher frequency of UPiD in rare disease cohorts. As a distinct mechanism underlying homozygosity compared to biallelic inheritance, the identification of UPiD has important implications for family planning and cascade testing. Our study demonstrates that UPD screening may improve diagnostic yields by prioritising UPiD chromosomes during WGS analysis.

A cohort study of neurodevelopmental disorders and/or congenital anomalies using high resolution chromosomal microarrays in southern Brazil highlighting the significance of ASD

“…The frequency of UPDs found in studies that used exome sequencing of patient-parent trios of large clinical populations for all sorts of genetic conditions is higher and oscillates between 0.2 and 0.6% 104 – 106 . The investigation for UPDs with whole genome sequencing of 164 parent–child trios in a more selected cohort, an Irish cohort with rare disorders, found 3 UPDs a frequency of 1.8% 105 .…”

“…Investigating 214,915 trios, from the 23andMe sequencing dataset, representing a non-clinical general population, the authors found 105 cases of UPD estimating that UPD occurs with an overall prevalence rate of roughly 1 in 2000 births or 0.05% 103 . The frequency of UPDs found in studies that used exome sequencing of patient-parent trios of large clinical populations for all sorts of genetic conditions is higher and oscillates between 0.2 and 0.6% [104][105][106] . The investigation for UPDs with whole genome sequencing of 164 parent-child trios in a more selected cohort, an Irish cohort with rare disorders, found 3 UPDs a frequency of 1.8% 105 .…”

A Cohort Study of Individuals with Neurodevelopmental Disorders and/or Congenital Anomalies Investigated by High- Resolution Chromosomal Microarrays in Southern Brazil: The Significance of Autism Spectrum Disorder

“…Investigating 214,915 trios, from the 23andMe sequencing dataset, representing a nonclinical general population, the authors found 105 cases of UPD estimating that UPD occurs with an overall prevalence rate of roughly 1 in 2,000 births or 0,05% [98]. The frequency of UPDs found in studies that used exome sequencing of patient-parent trios of large clinical populations for all sorts of genetic conditions is higher and oscillates between 0,2 and 0,6% [99][100][101]. The investigation for UPDs with whole genome sequencing of 164 parent-child trios in a more selected cohort, an Irish cohort with rare disorders, found 3 UPDs a frequency of 1.8% [100].…”

“…The frequency of UPDs found in studies that used exome sequencing of patient-parent trios of large clinical populations for all sorts of genetic conditions is higher and oscillates between 0,2 and 0,6% [99][100][101]. The investigation for UPDs with whole genome sequencing of 164 parent-child trios in a more selected cohort, an Irish cohort with rare disorders, found 3 UPDs a frequency of 1.8% [100].…”