Cardiff - Wales flyhalf Gareth Anscombe is to miss the Rugby World Cup with a serious knee injury, the Welsh Rugby Union announced on Monday.
The 28-year-old New Zealand-born playmaker suffered the injury in Sunday's 33-19 loss at Twickenham.
"Gareth Anscombe is out of Rugby World Cup contention after sustaining an Anterior Cruciate Ligament injury in the match against England yesterday," read the WRU statement on their website.
Anscombe's absence is a blow to the team's World Cup hopes. He was pivotal as Wales won last season's Six Nations Grand Slam.
"The Wales squad and management would like to wish Gareth the very best with his recovery," said the WRU statement.
Dan Biggar is the likely replacement for Anscombe in the starting line-up, the 29-year-old has more than 70 caps and came on to great effect in the Six Nations clash with England last season.
Anscombe is the second high-profile Wales casualty. Back-row forward Taulupe Faletau was ruled out earlier this month because of a collarbone injury.
There are 40 players remaining in head coach Warren Gatland's World Cup squad, which will be reduced to the final 31-strong party at the beginning of September.
Wales face England again in Cardiff on Saturday, followed by a double-header against Ireland in Cardiff on August 31 and Dublin on September 7.
Gatland - who brings the curtain down on his 12-year Welsh reign after the World Cup - and his side begin their World Cup campaign in Japan against Pool D opponents Georgia on September 23.
They play 2015 finalists Australia six days later, Fiji on October 9 and Uruguay four days after that.