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Complex genetic architecture in severe hypobetalipoproteinemia.

ABSTRACT: Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are phenotypically similar and are usually caused by bi-allelic mutations in MTTP and APOB genes, respectively. Instances of more complex patterns of genomic variants resulting in this distinct phenotype have not been reported.A 43 year-old male had a longstanding severe deficiency of apolipoprotein (apo) B-containing lipoproteins and circulating fat soluble vitamins consistent with either abetalipoproteinemia or homozygous familial hypobetalipoproteinemia (FHBL). He also had acanthocytosis, a long term history of fat malabsorption, and mild retinopathy, but was free from coagulopathy, myopathy and neuropathy. He had taken high dose oral fat soluble vitamins since childhood.Targeted next generation DNA sequencing revealed several rare heterozygous missense variants in both MTTP and APOB genes known or predicted to be deleterious, in addition to a novel heterozygous missense variant in SAR1B, which encodes the gene causing chylomicron retention disease. Evaluation of first degree relatives with mild FHBL clarified the segregation of variants.The proband's characteristic phenotype likely resulted from an oligogenic interaction involving multiple rare variants in MTTP and APOB, and related genes, each of which individually was associated with a milder or minimal clinical and biochemical phenotype.

SUBMITTER: Wang LR

PROVIDER: S-EPMC5853080 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Complex genetic architecture in severe hypobetalipoproteinemia.

Wang Linda R LR McIntyre Adam D AD Hegele Robert A RA

Lipids in health and disease 20180314 1

<h4>Background</h4>Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are phenotypically similar and are usually caused by bi-allelic mutations in MTTP and APOB genes, respectively. Instances of more complex patterns of genomic variants resulting in this distinct phenotype have not been reported.<h4>Methods</h4>A 43 year-old male had a longstanding severe deficiency of apolipoprotein (apo) B-cont ...[more]

PMID: 29540175

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Project description:Discovering links between the genotype of an organism and its metabolite levels can increase our understanding of metabolism, its controls, and the indirect effects of metabolism on other quantitative traits. Recent technological advances in both DNA sequencing and metabolite profiling allow the use of broad-spectrum, untargeted metabolite profiling to generate phenotypic data for genome-wide association studies that investigate quantitative genetic control of metabolism within species. We conducted a genome-wide association study of natural variation in plant metabolism using the results of untargeted metabolite analyses performed on a collection of wild Arabidopsis thaliana accessions. Testing 327 metabolites against >200,000 single nucleotide polymorphisms identified numerous genotype-metabolite associations distributed non-randomly within the genome. These clusters of genotype-metabolite associations (hotspots) included regions of the A. thaliana genome previously identified as subject to recent strong positive selection (selective sweeps) and regions showing trans-linkage to these putative sweeps, suggesting that these selective forces have impacted genome-wide control of A. thaliana metabolism. Comparing the metabolic variation detected within this collection of wild accessions to a laboratory-derived population of recombinant inbred lines (derived from two of the accessions used in this study) showed that the higher level of genetic variation present within the wild accessions did not correspond to higher variance in metabolic phenotypes, suggesting that evolutionary constraints limit metabolic variation. While a major goal of genome-wide association studies is to develop catalogues of intraspecific variation, the results of multiple independent experiments performed for this study showed that the genotype-metabolite associations identified are sensitive to environmental fluctuations. Thus, studies of intraspecific variation conducted via genome-wide association will require analyses of genotype by environment interaction. Interestingly, the network structure of metabolite linkages was also sensitive to environmental differences, suggesting that key aspects of network architecture are malleable.

Dataset Information

Complex genetic architecture in severe hypobetalipoproteinemia.

Publications

Complex genetic architecture in severe hypobetalipoproteinemia.

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