A novel autosomal recessive developmental disorder associated with pathogenic homozygous or compound heterozygous variants in the KPTN gene (MIM 615620) has recently been described as a dis

Background The genetic background of pulmonary arterial hypertension (PAH) in the Spanish pediatric population could be different from the genetic background described in other countries. Besides, clinical implications of a positive genetic result in the PAH pediatric population are not fully understood yet, and could result in the “reclassification” of patients from one PAH group to another type among the current pediatric classification. Material and methods Patients under 19 years at diagnosis included in the REHIPED registry from January 2011 to December 2021 were included. Clinical variables and genetical results were recorded. Succesive NGS panels involving up to 35 genes were used. After the results of the genetic testing, we analyzed differences in survival, and if patients “moved” to another category in the current Nice classification. Results In the selected cohort of 98 patients (56.1% female), median age at diagnosis was 7.1 years (IQr 1.5–14.7), and ethnicity as follows: Caucasian (81.6%), Romani (8.2%), others (10.2%) (Table 1). Before the genetic testing, patients had been classified as Idiopathic (53.1%), Congenital Heart Disease-PAH (30.6%), Heritable (5.1%), Pulmonary veno-oclusive disease (PVOD) 6.1%, and Multisystemic disorder associated with PAH (5.1%). Pathogenic or likely pathogenic variants were found in 44 of the screened patients (44.9%): BMPR2 (12 cases), EIF2AK4 (9), TBX4 (n=4), MECP2 (n=3), KCNK3 (n=2), FOXF1 (n=2), NFU1 (N=4), ACVRL1 (n=1), BMPR1B (n=1), CLBCI (n=1), GBE1 (n=1), GDF2 (n=1), SOX17 (n=1), VHL (n=1), and digenic pathogenic variant in ABCC8/SMAD1 (n=1). After genetic analysis, 28 patients (28.6%) were “reclassified” (Fig. 1, panel A), with HPAH, PVOD and multisystemic disorders increasing up to 18.4%, 8.2%, and 12.2%, respectively. Worse Survival from death or lung transplantation was observed in heritable PVOD and multisystemic disorders (Fig. 1, panel B). Conclusions The Spanish pediatric PAH population showed higher prevalence of EIF2AK4 than other pediatric registries. Genetic testing resulted in the “reclassification” of a significant number of patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rio Hortega grant from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III).

Introduction PAH is a severe complication of CTD, with remarkable morbidity and mortality. SSc is most commonly associated with PAH, but it can be present in other CTD. Despite major advances in PAH therapy, survival in CTD-PAH remains poor. Furthermore, the molecular and genetic basis of PAH in CTD are not well established. Purpose This study aimed to screen for genetic defects in a cohort of patients with CTD-PAH. Methods Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of PAH, and PVOD included in a national registry of PAH. A PAH-specific panel of 35 genes was designed. Results During enrolling, 79 patients were recruited: 59 SSc, 11 SLE and 9 other. 69 female, mean age 55,6±1,9 years, mean PVR 8,6±0,5 WU and mean DLCO 47,5±2%. Disease-associated variants were observed in 9 patients: 4 pathogenic/likely pathogenic in 4 different genes (TBX4, ABCC8, KCNA5 and GDF2/BMP9) and 5 VUS in 4 genes (ABCC8, NOTCH3, TOPBP1 and CTCFL). Clinical characteristics of patients with pathogenic/likely pathogenic variants and variant analyses are shown in Tables 1 and 2. Patient 1 is a Caucasian female with mixed CTD, diagnosed with PAH at 58 years of age. She has a frameshift pathogenic variant in TBX4. Pulmonary function test (PFT) ruled out interstitial lung disease (ILD), but a reduction in DLCO was observed (61% of predicted). Two patients carry variants in ABCC8. Patient 2 is a Caucasian female with SSc, diagnosed with PAH at 27 years of age. She carries a splicing variant in ABCC8, classified as likely pathogenic. Her mother was diagnosed with PAH associated with a repaired ASD at 61 years of age. In the genetic testing, no variants were observed in PAH genes. DLCO was 71% of predicted, without signs of ILD. Patient 3 is a Caucasian male, with clinical suspicion of PVOD associated with SSc and HIV infection. PAH was diagnosed at 57 years of age. He presented a missense variant in ABCC8, located in a gating regulatory region, and classified as VUS. Her sister was also diagnosed with PVOD associated with SSc at 48 years of age. No blood or tissue samples are available. In patient 3, DLCO was 22% of predicted value. CT scan showed the typical triad of PVOD. Patient 4 is a Latin American female with SLE, diagnosed with PAH at 25 years of age. She presented a pathogenic nonsense variant in GDF2/BMP9. Patient 5 is a Caucasian female with SSc, diagnosed with PAH at 70 years of age. She presented a pathogenic variant in KCNA5. Patients 6–9 have SSc-PAH and carry VUS in NOTCH1, CTCFL, CTCFL and TOPBP1, respectively. Conclusions We demonstrate the practical diagnostic utility of genetic testing with a panel in CTD-PAH. The discovery of rare variants in these patients forces us to take a comprehensive approach and accurate genetic counseling. Further research is still necessary to confirm these findings and help to provide a personalized medicine approach to these patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This project was founded by project “Bases Genético Moleculares de la Medicina de Precisiόn en la Hipertensiόn Arterial Pulmonar”. Funder: Instituto Carlos III. Ministerio de Economía y Competitividad.