Author:
Bernkopf Marie,Abdullah Ummi B.,Bush Stephen J.,Wood Katherine,Ghaffari Sahar,Giannoulatou Eleni,Koelling Nils,Maher Geoffrey J.,Thibault Loïc M.,Williams Jonathan,Blair Edward M.,Kelly Fiona Blanco,Bloss Angela,Burkitt-Wright Emma,Canham Natalie,Deng Alexander T.,Dixit Abhijit,Eason Jacqueline,Elmslie Frances,Gardham Alice,Hay Eleanor,Holder Muriel,Homfray Tessa,Hurst Jane A.,Johnson Diana,Jones Wendy D.,Kini Usha,Kivuva Emma,Kumar Ajith,Lees Melissa M.,Leitch Harry G.,Morton Jenny E. V.,Németh Andrea H.,Ramachandrappa Shwetha,Saunders Katherine,Shears Deborah J.,Side Lucy,Splitt Miranda,Stewart Alison,Stewart Helen,Suri Mohnish,Clouston Penny,Davies Robert W.,Wilkie Andrew O. M.,Goriely Anne
Abstract
AbstractNext-generation sequencing has led to a dramatic improvement in molecular diagnoses of serious pediatric disorders caused by apparently de novo mutations (DNMs); by contrast, clinicians’ ability to counsel the parents about the risk of recurrence in a future child has lagged behind. Owing to the possibility that one of the parents could be mosaic in their germline, a recurrence risk of 1-2% is frequently quoted, but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk stratification, by combining deep-sequencing of multiple tissues in the mother-father-child trio with haplotyping to determine the parental origin of the DNM. In the first 58 couples analysed (total of 59 DNMs in 49 different genes), the risk for 35 (59%) DNMs was decreased below 0.1% but for 6 (10%) couples it was increased owing to parental mosaicism - that could be quantified in semen (recurrence risks of 5.6-12.1%) for the paternal cases. Deep-sequencing of the DNM efficiently identifies couples at greatest risk for recurrence and may qualify them for additional reproductive technologies. Haplotyping can further reassure many other couples that their recurrence risk is very low, but its implementation is more technically challenging and will require better understanding of how couples respond to information that reduces their risks.
Publisher
Cold Spring Harbor Laboratory