Abstract Rationale Familial pulmonary fibrosis (FPF) is genetically heterogeneous. Genomics and telomere biology can inform risk, prognosis, and family counseling, yet real-world data from South America are scarce. Our objective was to implement and evaluate a clinic-ready genomic workflow (WES, targeted MUC5B, and telomere length) and report diagnostic yield in an Argentine FPF-enriched cohort. Methods Genomic DNA was extracted from peripheral blood leukocytes using the CTAB method. Adults with fibrosing ILD meeting ≥1 of the following were enrolled: (i) FPF by family history; (ii) age 50 with idiopathic fibrosing ILD; (iii) clinical features suggestive of short telomere syndrome. Whole-exome sequencing (WES) was performed by Macrogen on Illumina NovaSeq X platform using Twist Human Core Exome or Agilent SureSelect V6-Post capture kits (GRCh38 reference genome). Bioinformatic analysis focused on 47 genes previously associated with FPF, grouped by biological function: (i) telomere maintenance, (ii) surfactant biology, (iii) immune and inflammatory pathways, (iv) vesicular trafficking and lysosomal/autophagic function, (v) extracellular matrix and tissue integrity, (vi) aminoacyl-tRNA synthetases, and (vii) emerging or diverse functions. Variants were annotated using HGVS nomenclature and evaluated on the Franklin platform. Classification followed the ACMG/AMP guidelines and ClinGen expert panel specifications when available for the analyzed genes. The common MUC5B promoter variant (rs35705950), not captured by exome sequencing, was genotyped by targeted Sanger sequencing. Relative telomere length was measured by quantitative PCR (qPCR) using the telomere-to-single-copy-gene (T/S) ratio on genomic DNA from peripheral blood leukocytes. Results Thirty-one patients were analyzed (median age 65 years; IQR 59-70), predominantly with FPF. WES revealed rare heterozygous variants in 7 of 31 patients (22. 6%), distributed across the following genes: TERT (NM₁98253. 3: c. 430GA; p. Val144Met, likely pathogenic), RTEL1 NM₀01283009. 2: c. 1846GA; p. Gly616Ser, variant of uncertain significance (VUS) ; c. 2924GA; p. Gly975Asp, VUS, PARN (NM₀02582. 4: c. 19 + 5GA; p.? , VUS), AARS1 (NM₀01605. 3: c. 1811AG; p. Asn604Ser, VUS), MARS1 (NM₀04990. 4: c. 1000GA; p. Asp334Asn, VUS), and SFTPA1 (NM₀05411. 5: c. 637CT; p. Arg213*, VUS). The MUC5B promoter variant c. -3133GT (NM₀02458. 3; rs35705950; GRCh38: chr11: g. 1241221GT) showed genotype frequencies of GG 25. 8% (8/31), GT 67. 7% (21/31), and TT 6. 5% (2/31). Preliminary telomere qPCR testing identified short telomeres (5th percentile) in one individual. Conclusions In this first Argentine FPF-enriched cohort, a streamlined genomic pipeline was feasible and yielded informative variants in ∼23% of patients, with a high MUC5B risk-allele frequency consistent with global reports. Ongoing telomere testing and final variant curation will refine genotype-phenotype correlations and support clinical implementation in fibrosing ILD in Argentina This abstract is funded by: NONE
Enghelmayer et al. (Fri,) studied this question.