Genetic features of Japanese children with ABCA3 deficiency

ATP-binding cassette transporter A3 (ABCA3) deficiency is a rare form of interstitial lung disease caused by biallelic pathogenic variants in ABCA3, it is the most common cause of genetic surfactant deficiency among European and US infants and children. This study aimed to elucidate the genetic features of ABCA3 deficiency in Japanese children.

From April 2011 to March 2024, 291 candidates with children's interstitial lung disease (chILD) were enrolled. Sanger sequencing or next-generation sequencing for ABCA3 was performed for all candidates.

Eleven cases of ABCA3 deficiency were identified, including one pair of siblings. Among eight cases with onset at birth, five-including the siblings-died. All three cases whose disease onset occurred after 1 yr of age survived, and no cases presented between 1 month and 1 yr of age. Of the 11 cases, nine carried compound heterozygous ABCA3 variants. In the remaining two cases, diagnosed as ABCA3 deficiency based on specific pathological findings, only one pathogenic variant was detected in each. No homozygous variants were found, and aside from the siblings, no cases shared the same pathogenic variants. Eighteen distinct pathogenic variants were identified, including nine missense, five nonsense, three splicing, and one frameshift variant. All were considered disease-causing.

The incidence of ABCA3 deficiency among chILD candidates (11/291, 3.8%) was significantly lower (p < 0.0001) than those reported in the United States (185/632, 29.3%), Europe (79/398, 19.8%) and Argentina (14/50, 28%). The frequency of ABCA3 deficiency among Japanese children is low.