Introduction

Interstitial lung disease (ILD) encompasses a set of heterogeneous lung diseases characterized by infammation and/ or brosis of the lung parenchyma. Idiopathic pulmonarybrosis (IPF) is the most frequent idiopathic ILD after the age of 50. Evidence of a familial aggregation of ILD (i.e., familial interstitial pneumonia or familial pulmonary fbrosis (FPF)) suggests a role for genetic factors in the development of ILD. Over the past three decades, genetic discoveries in monogenic familial forms of FPF have led to signi cant insights into the role of inherited risk mutations in disease pathogenesis, and in the understanding of the intimate mechanisms of lung brosis, either idiopathic or non-idiopathic.

This chapter will focus on the main monogenic diseases associated with ILD with a particular focus on telomere-­ related genes and surfactant-associated protein gene mutations, the most frequent Mendelian disorders associated with ILD (Table 24.1, Fig. 24.2).

Table 24.1  Rare variants associated with interstitial lung disease

Fig. 24.2  Prevalence of (a) main genes and (b) corresponding pathways: TRG (telomeres related genes: TERT, TERC, RTEL1, etc.), surfactant (SFTPA, ABCA3, NKX2.1, etc.) and other miscellaneous

syndrome (COPA, TMEM173, etc.) with mutations associated with monogenic pulmonary brosis in adults

Familial Interstitial Pneumonia

Although there is no consensus de nition, FPF is usually de ned as a case of ILD in which the patient also has a family history of one or more relatives with ILD [1, 2]. Current studies report that familial forms of the disease account for 5–10% of IPF [3–5]. Adults with FPF are essentially ­indistinguishable from patients with sporadic IPF except that those with FPF tend to present earlier in life [6].

Male gender (55.7% vs. 37.2%, p < 0.0001), age (68.3 vs. 53.1 years, p < 0.0001), and cigarette smoking history (67.3% vs. 34.1%, p < 0.0001) were reported to be risk factors for developing ILD in a study of 111 FPF families, including 309 individuals with ILD and 360 unaffected relatives. Among ILD patients, a UIP pattern was identi ed in 85% patients; however, 45% of the families had two or more pathologic patterns identi ed, such as evidence of both UIP and NSIP histopathology [6]. Indeed several cohorts reported heterogeneity within families suggesting that distinct ILD categorizations may share similar pathogenesis pathways [7, 8]. The identi cation of cigarette smoking as a FPF risk fac-

tor also suggests that interaction between genetic predisposition and environmental exposures is central to the pathophysiology of ILD [6]. Many analyses of FPF families have suggested an autosomal dominant mode of inheritance with incomplete penetrance [6, 9, 10].

A single nucleotide polymorphism (SNP) rs35705950 located in the promoter region of the MUC5B gene is associated with an increased risk of FPF or sporadic IPF, with odds ratios (ORs) for disease of 6.8 (95% con dence interval [CI], 3.9–12.0) and 20.8 (95% CI, 3.8–113.7) for FPF and 9.0 (95% CI, 6.2–13.1) and 21.8 (95% CI, 5.1–93.5) for IPF, respectively [2]. This rs35705950 T risk allele is common in the Caucasian population, since it is detected in 9% of control individuals, but it is much less frequent in people of Asian origin [11, 12]. The rs35705950 variant is neither necessary nor suf cient to cause disease, suggesting a causative role for other genetic or environmental factors in disease development, but may explain 30% of the risk of developing lung brosis [13]. GWAS studies identi ed other polymorphisms associated with an increased risk of developing lungbrosis (Table 24.2) [14].