Small partial deletion of a highly GC-rich FOXF1 exon 1 in two deceased siblings with alveolar capillary dysplasia

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disorder caused by haploinsufficiency of FOXF1. While larger-sized coding and noncoding copy-number variant (CNV) deletions involving the FOXF1 locus are detected in approximately half of histopathologically-diagnosed ACDMPV patients, small CNVs remain diagnostically challenging. Here, we revisited an unsolved case of familial ACDMPV with two affected siblings. Whole genome sequencing (WGS) of 30-year-old archival lung autopsy tissue analyzed using AI powered platform revealed a 151 bp CNV deletion involving a highly GC-rich portion of exon 1 of FOXF1 that was not detected using Sanger sequencing and chromosomal microarray analysis. No evidence of parental somatic mosaicism was found. This case illustrates how small CNVs within GC-rich genomic regions can evade conventional diagnostic methods and demonstrates the advantage of hybridization free WGS with AI-based data analyses for resolving unsolved cases.