LAUSR

To the Editor Pulmonary arterial hypertension (PAH) is a rare and devastating disease, resulting from progressive obliteration of small pulmonary arteries leading to right heart failure. PAH can occur in the context of family history or pathogenic gene variants defining heritable PAH. Mutations in the BMPR2 gene are the most common cause representing more than 80% of familial forms of PAH and around 15% of sporadic PAH. Several other genes have been identified during the last decade. Here we report the case of a patient that was diagnosed with large perimembranous ventricular septal defect (VSD) at the age of 9 years. Her medical history included a transient ischemic stroke and scoliosis, without familial history of PAH, lymphedema or heart disease. There is no history of tobacco or toxic exposure. PAH associated with congenital heart disease (unrepaired VSD) was diagnosed when she was 25 and treated with endothelin receptor antagonist and phosphodiesterase type 5 inhibitor. After 10 years, the patient experienced clinical deterioration with right heart failure. Right heart catheterization showed severe precapillary PH with a mPAP of 59 mmHg, a low cardiac index (1.6 L/ min/m) and increased PVR of 19 WU. Six-minute walk distance was 120 m. Pulmonary function tests were normal except a mild decrease in diffusing lung capacity for carbon monoxide of 64%. Computed tomography of the chest revealed right ventricular dilatation and disseminated ground glass opacities (Figure 1(A)–(B)). Despite management in ICU with intravenous dobutamine, high flow nasal oxygenation, and urgent listing for heart-lung transplantation, the patient died after 40 days. We performed genetic testing by using a custom next-generation sequencing (NGS) targeted gene panel including all established PAH risk genes (ACVRL1, AQP1, ATP13A3, BMPR2, BMP10, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, TBX4) and additional genes related other hereditary vascular diseases. No pathogenic variant was identified in PAH genes. However, analysis revealed a heterozygous truncating variant (c.5544dup, p.Thr1849Aspfs*23) located in exon 12 in the laminin G protein domain of the Cadherin epidermal growth factor and laminin-G seven-pass G-type receptor 1 (CELSR1) gene (NM_001378328.1, GRch37, OMIM 604523) and resulting in the termination of CELSR1 protein at position 1872. This variant is classified as pathogenic according to ACMG guidelines since it is a predicted null variant, located in a conserved region and described only once in GnomAD v3.1.1 database in an individual of different ethnic origin (Latino/Admixed American). No DNA was available to perform segregation analysis in additional relatives including the parents of the index case. CELSR1 is a large 35-exon gene on human chromosome 22q13.31 The CELSR1 gene was included in our panel since loss-of-function variants were previously identified in hereditary primary lymphedema. CELSR1 variants have also been described in neural tube defects (NTD) and in patients with congenital heart defects (CHD). Variants identified in NTD and CHD are mainly missense variants. Functional analysis revealed that at least one of these missense variants (c.2609G>A p.P870L) identified in both NTD and CHD patients led to a gain of function effect. This suggests that mutations of different types can occur in the CELSR1 gene leading to contrasted functional consequences and various phenotypes. Previously found variants are located all along the gene without relationship between location and phenotype. The loss-offunction CELSR1 variant reported here has never been associated with lymphedema or other conditions.