Exome & General Genetics
Since 2011, clinical diagnostic exome sequencing (DES) has proven cost-effective and beneficial in providing molecular diagnoses for patients with a broad spectrum of previously undiagnosed genetic diseases and broadening the phenotype of known genetic diseases.1 Uniparental disomy (UPD) is a recognized clinically relevant finding most commonly diagnosed by methods such as methylation-specific polymerase chain reaction and methylation analysis.2,3 It is important to detect this phenomenon as it can result in imprinting disorders and/or homozygosity of rare recessive mutations.4 Multiple mechanisms have been documented that result in UPD.5,6 It can occur either as heterodisomy (UPhD) where two different homologous chromosomes are inherited from only one parent or as isodisomy (UPiD) where both homologs are identical due to duplication of one parental homolog (Figure 1A).5-7 A widely accepted rate of UPD is 1/3500 births, but a higher rate of 6/1057 has recently been observed in a cohort of patients from the Deciphering Developmental Disorders project, suggesting that clinical cohorts have an enhanced rate of UPD.7-9 Herein, we report a patient presenting with multiple congenital anomalies with a paternally inherited heterozygous truncating mutation in the GLI family zinc finger 2 (GLI2) gene as well as maternal primary UPiD (centromeric isodisomy and distal heterodisomy) of chromosome 20 detected by clinical DES.