Idiopathic interstitial pneumonias (IIPs) are diffuse lung diseases of unknown cause and high mortality. Up to 20% of patients with IIP report having one or more family members with the disease (1, 2), referred to as familial interstitial pneumonia (FIP). Genetic analysis has previously revealed deleterious mutations in surfactant protein A2 (SFTPA2) in two families (2). Here, we report the genetic analysis of SFTPA2 in a cohort of familial and sporadic patients with IIP. All coding regions of SFTPA2 were sequenced in a cohort of 39 unrelated patients with FIP and 118 sporadic patients with IIP, using previously published primers (2). FIP was defined as two or more first-degree family members with IIP. Diagnoses were established using current classification guidelines (3, 4). Patients with mutations in SFTPC, TERT, TERC, or TINF2 were not included. The control cohort comprised 100 healthy white Dutch subjects. The Ethical Committee of St. Antonius Hospital approved the study, and all subjects gave written informed consent. In the FIP cohort, we identified three new mutations in exon 6 of SFTPA2: N210T, G231R, and N171Y. Mutation carriers were heterozygous for the mutation. In the sporadic IIP cohort, one heterozygous carrier of the mutation, N210T, was discovered; none of the mutations was detected in Dutch controls or in any of the public databases representing more than 60,000 individuals worldwide (Table 1). All three mutations caused nonsynonymous amino acid substitutions that were predicted to have deleterious consequences in silico by the programs Sorting Intolerant from Tolerant (SIFT)(5) and PolyPhen-2 (6)(Table 1). We additionally evaluated in silico all seven common and unique nonsynonymous SFTPA2 variants that were identified by Wang and coworkers (2). In contrast to common polymorphisms, only mutations F198S and G231V were predicted to have deleterious consequences in both SIFT and PolyPhen-2 (Table 1). Patient FPF5 carried mutation SFTPA2 N210T (Figure 1A). He was a 40-year-old man with a pattern of nonspecific interstitial pneumonia (NSIP; Figure 1B) on high-resolution computed tomography (HRCT) and usual interstitial pneumonia (UIP) with features of desquamative interstitial pneumonia (DIP) on biopsy. Sixty-four months after diagnosis, he underwent unilateral lung transplantation of the left lung. Posttransplantation, he soon developed severe primary graft dysfunction and respiratory failure. Therefore, a rescue bilateral retransplantation was performed. Pathological examination of the explanted native right lung revealed a poorly differentiated adenocarcinoma situated in the right lower lobe with invasive growth into the pleural wall. Furthermore, five intrapulmonary lymph nodes and three hilar lymph nodes were tumor positive. No malignancy was found in the native left lung. The patient died 19 months after lung transplantation as a result of metastasized lung cancer. In the sporadic IIP cohort, an identical SFTPA2-N210T mutation was present in a 67-year-old male patient. His father had died from lung cancer, and his mother had suffered from chronic obstructive pulmonary disease. Patient demographics of this patient and FPF5 differed up to two generations back, but genetic analysis could not exclude the possibility of a common ancestor. Our second SFTPA2 mutation, G231R, was found in patient FPF15 (Figure 1A), a 43-year-old man. HRCT showed a pattern of NSIP (Figure 1C) and UIP on biopsy (Figure 1F). Fourteen months after diagnosis, he developed an area of consolidation (Figure 1E), and he died 18 months after diagnosis of respiratory insufficiency. Autopsy demonstrated an adenocarcinoma …