Whole-exome sequencing as diagnostic tool in a quartet family with Abetalipoproteinemia

Abetalipoproteinemia (ABL) is a rare lipid metabolism disease, where mutations in causative known genes can only explain a low percentage of cases. This disease is characterized by very low plasma concentrations of triglycerides and total cholesterol (under 30mg/dl), and undetectable levels of LDL and ApoB. Later in life, ABL is associated with atypical development of retinitis pigmentosa, coagulopathy, column neuropathy and myopathy.

We used whole-exome sequencing (WES) to study a family with two affected children and their asymptomatic parents. Mutations in causative known genes for ABL (MTTP) and for diseases with similar phenotype such as Familial Hypobetalipoproteinemia (APOB, PCSK9 and ANGPTL3) have been previously discarded by Sanger sequencing.

By examining homozygous and compound heterozygous inherited variants, we found that both children carried mutations in SEC23A gene. Recent studies have demonstrated that SEC23A, an essential component of coat protein complex II (COPII)-coated vesicles, could be involved in the apoB100-lipoproteins exit from the endoplasmic reticulum to de Golgi apparatus.

Besides, SEC23A has been associated with Craniolenticulosutural dysplasia (CLSD), disorder characterized by late-closing fontanels among other features. Since both children showed unexplained late-closing fontanels, our study strongly indicate that SEC23A could be a new ABL causative gene not previously described. Functional assays are currently being developed for both genes to confirm these results.