Diagnosis of lethal or prenatal-onset or familial coinciding recessive disorders by parental exome sequencing

Background and Aim : In the case of familial history of probable genetic disorders, recurrence risk assessment and carrier detection depend on the identification of causative mutation in affected relatives. However, prior death of some cases, precludes genetic study. In this situation, testing of expected obligate carrier parent(s) is regarded as an appropriate alternative. Also healthy parent may be preferred to affected offspring for genetic testing, because of simultaneous more likelihood of carrying other mutant alleles due to closer relationship to family members with other genetic disorders.Methods : Exome sequencing was carried out in a consecutive series of 12 healthy parents with probable AR or XLR inherited diseases in their offspring who died prenatally or any time before genetic testing and/or had 2 or more different genetic disorders in their children and close relatives. The mothers were prioritized for whole exome sequencing (WES), except negligible XLR inheritance probability for offspring s disease and greater chance of carrying other mutant alleles by husband. Heterozygous variants were tested in spouse and live affected offspring to evaluate segregation. If both of parents had heterozygous known (KP) or likely pathogenic (LP) variants in common, they were considered as causative mutations; even though because of DNA unavailability, the zygosity of deceased child remained obscure. Parental shared variants of unknown significance (VUSs) were interpreted as probable or possible disease-causing, whether homozygosity of affected offspring, could be approved or not.Results : 12 couples reported 14 genetic diseases in their children, for 4 of them (and either of 8 diseases described in other relatives) no relevant variant was found. For other 10 diseases, 5 KP/LP variants and 11 VUSs were identified. Segregation analysis confirmed causative role of the first group and suggested 2 & 2 VUSs as probable & possible disease-causing, respectively. Two variants were detected in a single case. So, the current study revealed up to 57% diagnostic yield for parental solo-WES.Conclusion : Seemingly, exome sequencing of parental samples has acceptable clinical utility for the genetic diagnosis of lethal or prenatal-onset or concurrent recessive disorders in offspring.