Mendelian causes of early-onset emphysema: a review of the current literature

Currently, the only known clinically relevant hereditary risk factor for emphysema is limited to mutations within the <i>SERPINA1</i> gene, encoding alpha-1 antitrypsin. Although several additional rare high-impact variants have been proposed, their role in emphysema pathophysiology is unclear. This review discusses recent cases investigating novel candidate genes that may be Mendelian causes for emphysema development. We also explore potential methods to confirm the causal relation to COPD. Identifying potential new rare high-impact genetic variants may lead to novel therapeutic targets, thus improving the personalised treatment of COPD. Several gene mutations have been implicated in emphysema development, including <i>SERPINA1</i>, <i>SERPINA3</i>, <i>PTPN6</i>, <i>TERT</i>, <i>TR</i>, <i>NAF1</i>, <i>BICD1</i>, <i>ELN</i>, <i>FBLN</i>, <i>FLNA</i> and <i>SFTPC</i> Mutations of the <i>SERPINA1</i> and <i>PTPN6</i> genes are considered definitive causes of emphysema. Studies have ascertained rare variants in cutis laxa genes (<i>ELN, FBLN</i> and <i>FLNA)</i>, which cause early-onset emphysema in infants and children <i>via</i> defective elastin synthesis. Telomerase pathway genes (<i>TERT</i>, <i>TR</i>, <i>NAF1</i> and <i>BICD1</i>) have also been implicated in increased COPD risk along with another member of the serpin family (<i>SERPINA3</i>) and <i>SFTPC</i> These probable mutations for emphysema tend to present later in life. Due to being unconfirmed, they may involve a more complex gene interaction that requires further interrogation with next-generation sequencing and molecular methods, including CRISPR (clustered regularly interspaced short palindromic repeats) screening libraries, whole-exome sequencing or whole-genome sequencing. Although multiple novel mutations have been reported to cause emphysema, further validation is needed. Next-generation sequencing offers a promising method to understand early-onset emphysema and COPD pathogenesis.