Differences in genetic characteristics between Chinese and non-Chinese patients with pulmonary alveolar microlithiasis-case series and a systematic review.

Background: Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disorder caused by SLC34A2 variants, characterized by diffuse alveolar calcium phosphate deposits. While the SLC34A2 mutation spectrum has been well-documented, the distinct variant landscape in Chinese patients remains unclear.

Objectives: This study aims to report three newly identified PAM cases and describe the SLC34A2 mutation spectrum of Chinese PAM patients through a systematic review.

Design: We documented the diagnosis and treatment processes and genetic variations of three PAM cases for reporting. Furthermore, we searched academic websites for published PAM cases with SLC34A2 variants and extracted clinical and genetic data for analysis.

Methods: We employed whole-exome sequencing to identify genetic mutations of these three patients. We systematically searched PubMed, Web of Science, China National Knowledge Infrastructure, and Cochrane Library for published PAM cases with SLC34A2 mutations. Clinical and genetic data were extracted into an Excel database and analyzed using SPSS 23.0 software (IBM, Armonk, NY, USA).

Results: Among the three cases we reported, two homozygous mutations in SLC34A2-c.910A>T (p.Lys304*) in exon 8 and c.575C>A (p.Thr192Lys) in exon 6 were identified. Analysis of 27 Chinese and 49 non-Chinese PAM patients revealed similar clinical manifestations, but a strikingly distinct genetic spectrum. Compound heterozygous mutations predominated in Chinese patients, while only two cases of compound heterozygous mutations were found in non-Chinese patients. Deletion/insertion mutations are the most common in non-Chinese patients (19/47, 40.4%), whereas nonsense mutations are the most frequent in Chinese patients (12/20, 60%). Further analysis of the reported SLC34A2 mutation sites in Chinese PAM patients showed hotspot regions in exons 5, 6, and 8, with c.910A>T in exon 8 being a unique gene screening target in Chinese patients.

Conclusion: This study delineates a distinct spectrum of SLC34A2 mutations in Chinese PAM patients, highlighting the importance of ethnicity-specific genetic screening in PAM diagnosis.