Abstract 11571: Whole Exome Sequencing in Familial Hypobetalipoproteinemia

Abstract

Background: Whole exome sequencing (WES) has shown ~30% success in the diagnosis of Mendelian disorders. Few data exists regarding clinical application of WES for the molecular diagnosis of familial hypobetalipoproteinemia (FHBL), which is characterized as extremely low LDL cholesterol level. Methods: WES was performed on 36 individuals including 32 patients exhibiting low LDL-C (less than 70 mg/dl) primarily, and 4 unaffected family members from 23 families. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the autosomal codominant pattern; 4) C-score < 10 calculated using in silico prediction software named Combined Annotation Dependent Depletion. Results: Among 181,404 variants found in those individuals, we found 48,786 nonsense, missense, or splice site variants, of which 14,415 were rare (MAF ≤ 1% or not reported). Filtering assuming autosomal codominant pattern of inheritance combined with the use of C-score, we identified heterozygous mutations in 7 families, and homozygous or compound heterozygous mutations in 4 families within the coding region of APOB gene, eight of which were novel (c.394A>T/p.Lys132*, c.1902_1903delTC/p.Ser634fs, c.2702T>G/p.Met901Arg, c.2946delC/p.Ser982fs, c.4437G>C/p.Leu1479Phe, c.4439_4440delTT/p.Phe1480fs, c.11283C>A/p.Cys3761*, c.11433dupT/p.Glu3812fs). Moreover, we identified compound heterozygous mutations in 1 family within the coding region of PCSK9 gene, one of which was novel (c.1301G>A/p.Arg434Gln). Conclusion: WES combined with integrated variant annotation prediction successfully identified causative mutations in patients with FHBL either with APOB gene mutation(s) or PCSK9 gene mutation(s) in 12 among 23 families (52%). Although such comprehensive approach is useful to determine true causative mutations, other strategies are needed to identify novel causative genes, which could potentially lead to the development of novel pharmacological target for dyslipidemia.