Familial lecithin-cholesterol acyltransferase deficiency: If so rare, why so frequent in the state of Piauí, northeastern Brazil?

Abstract

Lecithin-cholesterol acyltransferase (LCAT), an enzyme that participates in lipoprotein metabolism, plays an important role in cholesterol homeostasis. Mutations in the LCAT gene can cause two rare genetic disorders: familial LCAT deficiency (FLD), which is characterized by corneal opacities, normocytic anemia, dyslipidemia, and proteinuria progressing to chronic renal failure, and fish-eye disease (FED), which causes dyslipidemia and progressive corneal opacities. Herein, we report six suspected cases of FLD in the backlands of Piauí, located in northeast Brazil. A genetic diagnosis was performed in index cases. Among these, a further investigation was performed to identify new cases in the families. In addition, molecular analyses were performed to verify the levels of consanguinity within families and the existence of a genetic relationship between them. All six index cases were confirmed as FLD with an identical mutation (c.803G > A, p.R268H). The genetic investigation confirmed another 7 new cases of FLD, 52 heterozygous and 6 individuals without mutations. The rate of consanguinity revealed that marriages within the family did not contribute to the high number of FLD cases within the restricted region. The elders of each family (patriarchs and matriarchs) were subjected to a kinship analysis and were more genetically related to each other than the control group. Bayesian analysis was implemented to confirm the hypothesis of connectivity among patriarchs and matriarchs and indicated that they were genetically more related to each other than would be randomly expected, thus suggesting the occurrence of a possible founder effect in these families.

Keywords: Chronic kidney disease; FED, Fish-eye disease; FLD, familial lecithin-cholesterol acyltransferase deficiency; Genetic relatedness; HDL, high-density lipoprotein; High-density lipoproteins; LCAT, lecithin-cholesterol acyltransferase; Lecithin-cholesterol acyltransferase; Mutation; Rare disease.

Fig. 1

Pedigree of six families with a molecular diagnosis of familial LCAT deficiency. Squares indicate males; circles indicate females; diamond indicates unspecified sex; filled symbols indicate homozygote carriers; half-filled symbols indicate heterozygote carriers; white symbols indicate noncarrier individuals; slashed symbols indicate deceased individuals; squares and circles with gray borders indicate individuals not available for analysis. LCAT, lecithin-cholesterol acyltransferase.

Fig. 2

Medium kinship within families (F01 to F05), between elders of each family and negative controls (NC).

Fig. 3

Genetic cluster analysis between elders of each family and negative controls, considering the existence of 2 to 7 genetic groups (K). The bars above each individual indicate its membership probabilities on a scale of 0.0 to 1.0 considering each tested K. The number of colors presented in the chart is equivalent to the number of K.

Fig. 4

Map of Brazil highlighting the state of Piauí with an approximation revealing the proximity of locations where each family resides. Geographical coordinates of cities: F01 (−7.087542083096411, −43.50913433343056), F02 (−8.134889003994939, −41.14333225657599), F03 (−7.777304608346234, −43.137239317995984), F04 (−7.716868748179102, −41.34969456403206), F05 (−7.966926843069498, −40.872506199431974) and F06 (−8.141389765084043, −40.79823034193549).