Complex genetic architecture in severe hypobetalipoproteinemia.

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia (FHBL) are typically caused by bi-allelic mutations in MTTP and APOB genes, respectively.
• These autosomal recessive and co-dominant conditions present with similar phenotypes, characterized by severe deficiencies in apolipoprotein B-containing lipoproteins.

Observation:

• A 43-year-old male presented with severe deficiency of apolipoprotein B-containing lipoproteins and fat-soluble vitamins, alongside acanthocytosis, fat malabsorption, and mild retinopathy.
• The patient had no coagulopathy, myopathy, or neuropathy and had taken high-dose fat-soluble vitamins since childhood.

Findings:

• Next-generation DNA sequencing identified rare heterozygous missense variants in MTTP and APOB, along with a novel heterozygous missense variant in SAR1B.
• Segregation analysis in first-degree relatives with mild FHBL helped clarify the inheritance pattern of these variants.

Implications:

• The proband's phenotype is likely due to an oligogenic interaction, where multiple rare variants in MTTP, APOB, and related genes contribute to the clinical presentation.
• This case highlights that complex genomic variant interactions, not just bi-allelic mutations, can lead to severe lipoprotein deficiency phenotypes.