Molecular basis of the familial chylomicronemia syndrome in patients from the National Dyslipidemia Registry of the Spanish Atherosclerosis Society

• Published in: Journal of clinical lipidology Vol. 12; no. 6; pp. 1482 - 1492.e3
• Main Authors: Ariza, María José, Rioja, José, Ibarretxe, Daiana, Camacho, Ana, Díaz-Díaz, José Luis, Mangas, Alipio, Carbayo-Herencia, Julio A., Ruiz-Ocaña, Pablo, Lamíquiz-Moneo, Itziar, Mosquera, Daniel, Sáenz, Pedro, Masana, Luis, Muñiz-Grijalvo, Ovidio, Pérez-Calahorra, Sofía, Valdivielso, Pedro, Suárez Tembra, M., Iglesias, Gonzalo Pías, Carbayo Herencia, J.A., Guerrero Buitrago, C., Vila, L., Morales Coca, C., Llargués Rocabruna, E., Perea Castillo, V., Pedro-Botet, J., Climent, E., Mauri Pont, M., Pinto, X., Ortega Martínez de la Victoria, E., Amor, J., Zambón Rados, D., Blanco Vaca, F., Ramiro Lozano, J.M., Fuentes Jiménez, F.J., Soler, I., Ferrer, C., Zamora Cervantes, A., Vila Belmonte, A., Novoa Mogollón, F.J., Sanchez-Hernández, R.M., Expósito Montesdeoca, A.B., Romero Jiménez, M.J., González García, M.P., Bueno Díez, M., Brea Hernando, A., Lahoz, C., Mostaza Prieto, J., Millán Núñez-Cortés, J., Reinares García, L., Blanco Echevarría, A., Ariza Corbo, María José, Rioja Villodres, J., Sánchez-Chaparro, M.A., Jansen Chaparro, S., Sáenz Aranzubía, P., Martorell Mateu, E., Almagro Múgica, F., Muñiz Grijalvo, O., Masana Martín, L., Plana Gil, N., Ibarretxe Gerediaga, D., Rodríguez Borjabad, C., Zabala López, S., Hernández Mijares, A., Ascaso Gimilio, J.F., Pérez García, L., Civeira Murillo, F., Pérez-Calahorra, S., Lamiquiz-Moneo, I., Mateo Gallego, R., Marco Benedí, V., Ferrando Vela, J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2018
• Subjects: Candidate genes; Causative mutation; Familial chylomicronemia syndrome; LPL activity; LPL mass; LPL activity; Causative mutation; LPL mass; Candidate genes; Familial chylomicronemia syndrome
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2018.07.013

Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex.
This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry.
Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5).
Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326_327insC; p.Tyr110Leufs*158).
We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS.
•We studied data from the Spanish Atherosclerosis Society Dyslipidemia Registry.•We diagnosed 26 patients with familial chylomicronemia syndrome.•We identified 5 novel mutations in LPL (2), GPIHBP1 (1), and APOA5 (2).•Twenty-three patients were homozygous for mutations in LPL (19) and GPIHBP1 (4).•Three patients heterozygous for mutations in LPL or APOA5 had LPL activity deficiency.