In 2023, Novartis hired Sigler to star in a TV commercial for their multiple sclerosis drug Kesimpta. This symptom turned out to be related to multiple sclerosis, but it was misdiagnosed as Lyme disease at the time. In 2000, while filming Campfire Stories in Hamburg, New Jersey, Sigler was paralyzed from the waist down for several days. In January 2016, Sigler revealed that she was diagnosed with multiple sclerosis when she was 20 years old. The couple had their second son on January 15, 2018. They were married in Palm Springs, California, on January 16, 2016. Sigler gave birth to their first son on August 28, 2013. The two became engaged on January 28, 2013, and announced in February 2013 that they were expecting their first child. In 2012, Sigler began dating baseball player Cutter Dykstra, the son of former Major League Baseball player Lenny Dykstra. She later dated football player Mark Sanchez. Also in 2008, she began a relationship with actor Jerry Ferrara, whom she met while guest-starring on Entourage as a love interest of Ferrara's character. She said that the trip gave her a greater understanding of her Jewish ancestry. In 2008, Sigler visited Israel through the Birthright Israel program and was moved by the trip, calling Israel 'one of the most beautiful, inspiring places ever been to'. She then dated restaurateur Scott Sartiano from 2006 to 2008. They separated in September 2005, and she resumed using her maiden name. She subsequently changed her name to Jamie-Lynn DiScala. They began dating shortly before she turned 21, and married on July 11, 2003. Sigler met Abraxas 'A.J.' DiScala when she was 19, and he became her manager. In 2024, Sigler began a podcast with fellow actress with multiple sclerosis Christina Applegate called MeSsy about their friendship based on the condition. In 2002, Sigler co-authored her autobiography, Wise Girl: What I've Learned About Life, Love, and Loss. In 2012, she collaborated with Romeo Santos on the single 'You' and appeared in its music video. In 2001, Sigler released a pop album called Here to Heaven, which featured the single 'Cry Baby.' The album was a commercial failure.

In 2020, Sigler starred as a featured player in the Adult Swim sitcom Beef House. In 2019, Sigler appeared on the game show Pyramid alongside Steve Schirripa. From 2012 to 2013, she appeared as a main character in the short-lived series Guys with Kids. The same year, she appeared on ABC's Ugly Betty in a five-episode arc. In 2009, Sigler starred in the psychological thriller film Beneath the Dark, which originally had a working title of Wake. On the December 6, 2008, airing of Saturday Night Live, she appeared as the checkout girl for the Digital Short music video ' Jizz in My Pants' by The Lonely Island. On November 17, 2008, Sigler guest-starred as Jillian on the TV series How I Met Your Mother in the episode ' Woooo!'. She returned as a recurring guest star for season six of the series, after becoming Ferrara's real-life girlfriend. In the fifth season, she appeared as the love interest of the character Sal 'Turtle' Assante, portrayed by Jerry Ferrara. In 2008, Sigler appeared as herself in 13 episodes of the fifth and sixth season of the HBO series Entourage. In 2005, Sigler starred in Love Wrecked and the following year in Homie Spumoni, when she played the role of Alli, the girlfriend of Renato/Leroy ( Donald Faison) directed by Mike Cerron. In that same year, she had her first starring feature film role, Extreme Dating, an independent film. In 2004, Sigler starred as 'Hollywood Madam' Heidi Fleiss in the USA television movie Call Me: The Rise and Fall of Heidi Fleiss. She then spent five months on Broadway from October 2002 through February 2003 playing Belle in Beauty and the Beast. Sigler played the title role in Cinderella on tour and at The Theatre at Madison Square Garden in 2001. She continued to play the role through the series finale in 2007. When her manager first told her about auditioning for The Sopranos, Sigler thought she would have to sing soprano. In 1997, Sigler was cast as Meadow Soprano, daughter of New Jersey mob boss Tony Soprano on the HBO series The Sopranos. She attended Jericho High School and studied at the Cultural Arts Playhouse in Old Bethpage, New York. Sigler's mother was raised Catholic but converted to Judaism upon marrying Sigler's father. Sigler is of Greek-Jewish and Romanian-Jewish descent through her father, and of Cuban descent through her mother. Her father was the founder of the Men's Senior Baseball League. Sigler was born in Jericho, New York, on May 15, 1981, the daughter of Steve and Connie Sigler. She is best known for her role as Meadow Soprano on the HBO series The Sopranos. Jamie-Lynn Sigler (born May 15, 1981) is an American actress.

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