Complex genetic architecture in severe hypobetalipoproteinemia

Table 1 Heterozygous rare variants detected in atypical hypobetalipoproteinemia proband

gene/chr	exon	cDNA change	amino acid	ExAC MAF(A)	CADD	SIFT	PolyPhen-2	comments
APOB/2p24	10	c.T1223C	p.I408T	0.0268	15.7	0.211	0.065	uncommon missense variant; possibly pathogenic [17]
	26	c.G6895C	p.D2299H	0.0215	19.6	0.062	0.98	uncommon missense variant; possibly pathogenic [17]
	26	c.A7242C	p.E2414D	0.0076	11	0.405	0.007	uncommon missense variant; unlikely pathogenic
	29	c.T12803C	p.M4268T	0.0076	0.001	0.485	0	uncommon missense variant; unlikely pathogenic [17]
MTTP/4q23	13	c.G1769T	p.S590I	NP	28.5	0.034	0.996	very rare proven dysfunctional variant [7, 9]
PCSK9/1p32	8	c.G1327A	p.A443T	0.0981	9.68	0.534	0.004	variant of unknown significance
SAR1B/5q31	5	c.A314G	p.H105R	NP	9.84	1	0	variant of unknown significance
ANGPTL3/1p31	4	c.T776C	p.M259T	0.0542	3.46	0.084	0.001	variant of unknown significance

Abbreviations: chr Chromosomal locus, cDNA Coding DNA sequence, APOB Gene encoding apolipoprotein B, MTTP Gene encoding microsomal triglyceride transfer protein, PCSK9, Gene encoding proprotein convertase subtilisin kexin 9, SAR1B Gene encoding S. cerevisiae homolog B (chylomicron retention disease gene), ANGPTL3 Gene encoding angiopoietin-like protein 3, ExAC Exome aggregation consortium [18] (url: http://exac.broadinstitute.org/), MAF(A) Minor allele frequency in African populations, NP Not present in database, CADD Combined annotation dependent depletion algorithm [5] (url: http://cadd.gs.washington.edu/), SIFT Sorting intolerant from tolerant algorithm [6] (url: http://sift.jcvi.org/), PolyPhen-2 Polymorphism phenotyping tool version 2 [19] (url: http://genetics.bwh.harvard.edu/pph2/)
Explanation of predictive functional scores: A CADD score > 20 is predicted to be in the top 1% of most deleterious substitutions within the human genome. A CADD score from 10 to 20 is predicted to be in the top 10% of most deleterious substitutions within the human genome. A SIFT score ≤ 0.05 is considered to be ‘deleterious’; while a score ≥ 0.05 is considered to be ‘tolerated’. A PolyPhen-2 score of 0.957 to 1.0 is considered to be ‘probably damaging’; of 0.454 to 0.956 is considered to be ‘possibly damaging’ and of 0.0 to 0.453 is considered to be ‘benign’

ISSN: 1476-511X