Journal Article

Phenotypic severity in a family with MEND syndrome is directly associated with the accumulation of potentially functional variants of cholesterol homeostasis genes

Garza‐Guajardo, Raquel, Barboza‐Quintana, Oralia, Martínez‐Aldape, Gerardo, Barboza‐Cerda, María Carmen, Déctor, Miguel Angel

2019

Overview

Background Male EBP disorder with neurologic defects (MEND) syndrome is an X‐linked disease caused by hypomorphic mutations in the EBP (emopamil‐binding protein) gene. Modifier genes may explain the clinical variability among individuals who share a primary mutation. Methods We studied four males (Patient 1 to Patient 4) exhibiting a descending degree of phenotypic severity from a family with MEND syndrome. To identify candidate modifier genes that explain the phenotypic variability, variants of homeostasis cholesterol genes identified by whole‐exome sequencing (WES) were ranked according to the predicted magnitude of their effect through an in‐house scoring system. Results Twenty‐seven from 105 missense variants found in 45 genes of the four exomes were considered significant (−5 to −9 scores). We found a direct genotype–phenotype association based on the differential accumulation of potentially functional gene variants among males. Patient 1 exhibited 17 variants, both Patients 2 and 3 exhibited nine variants, and Patient 4 exhibited only five variants. Conclusion We conclude that APOA5 (rs3135506), ABCA1 (rs9282541), and APOB (rs679899 and rs12714225) are the most relevant candidate modifier genes in this family. Relative accumulation of the deficiencies associated with variants of these genes along with other lesser deficiencies in other genes appears to explain the variable expressivity in MEND syndrome. To explain the intrafamilial phenotypic variability in MEND syndrome, we performed whole‐exome sequencing (WES) for four related patients, each of whom represented a different degree of phenotypic severity. Variants of the homeostasis cholesterol genes were ranked according to the predicted magnitude of their effect through an in‐house scoring system. We found a direct genotype‐phenotype relationship based on the differential accumulation of the potentially functional gene variants which appears to explain the degree of phenotypic severity among patients

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: ABCA1 / ABCA1 protein / Accumulation / APOA5 / APOB / Apolipoprotein A-V - genetics / Apolipoprotein A-V - metabolism / Apolipoprotein B-100 - genetics / Apolipoprotein B-100 - metabolism / Apolipoproteins / ATP Binding Cassette Transporter 1 - genetics / ATP Binding Cassette Transporter 1 - metabolism / ATP-binding protein / Biosynthesis / Cholesterol / Cholesterol - genetics / Cholesterol - metabolism / Disease / emopamil‐binding protein / Exome / Female / Gene sequencing / Genes / Genetic Association Studies / Genetic variability / Genotype & phenotype / Genotypes / Homeostasis / Homeostasis - genetics / Humans / Intellectual disabilities / Ligands / Lipoproteins / Male / Males / MEND syndrome / modifier genes / Mothers / Mutation / Original / Phenotype / Phenotypes / Placenta / Polymorphism, Genetic / Severity of Illness Index / Sterols / Waardenburg Syndrome - genetics / Waardenburg Syndrome - metabolism / Waardenburg Syndrome - pathology