A 5-year-old girl was referred to a pediatric gastroenterology clinic for chronic constipation and poor weight gain. During her first week of life, she developed diarrhea and vomiting. With initiation of solid food, she developed laxative-dependent constipation. She underwent newborn genetic screening before routine cystic fibrosis (CF) screening. Results were normal. At the time of presentation to the gastroenterology clinic, she had no respiratory symptoms. Results of anorectal manometry, spinal magnetic resonance imaging, and thyroid studies were normal. Family history included constipation in a sister and a great aunt with CF. Her body mass index (BMI) was below the third percentile (eFigureA in the Supplement). Physical examination findings were unremarkable, including normal respiratory examination. Fecal elastase level was within reference range (>500 μg/g); abdominal computed tomographic image revealed a dilated, tortuous sigmoid colon; and full-thickness rectal biopsy was negative for Hirschsprung disease. She was referred for sweat chloride testing to assess for CF. Results of 3 separate sweat chloride tests were indeterminate (Table), prompting pulmonology referral. A 97-mutation CF transmembrane conductance regulator (CFTR) analysis panel was negative. Whole-genome sequence analysis revealed 1 CF-causing mutation (c.2249C>T) and 2 likely benign variants (c.1408A>G and c.2562T>G).