Highlights
- •Whole exome sequencing successfully identified asymptomatic Tangier disease.
- •Such comprehensive approach is useful to determine causative variants.
- •Patients with HDL deficiency have great diversities in their clinical phenotype.
Abstract
Objective
Molecular diagnosis for subjects with extremely low HDL-C through candidate-gene approaches
requires huge effort. Whole exome-sequencing (WES) has already shown approximately
∼30% success in the diagnosis of Mendelian disorders. Moreover, novel in silico prediction software for the pathogenicity of novel missense variants named Combined
Annotation Dependent Depletion (CADD) has recently been developed, enabling the objective
integration of many diverse annotations into a single measure (C-score) for each variant.
Here, we investigated whether WES combined with integrated variant annotation prediction
could facilitate the molecular diagnosis of this rare condition.
Methods
WES was performed on 8 individuals including 2 individuals exhibiting extremely low
HDL-C (2 mg/dl and 6 mg/dl), 2 unaffected family members, and 4 unrelated individuals
as controls. We filtered out the following variants: 1) Benign variants predicted
by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the
recessive form of inheritance; 4) C-score < 10.
Results
Among 305,202 variants found in those individuals, we found 21,708 nonsense, missense,
or splice site variants, of which 5192 were rare (MAF ≤ 1% or not reported). Filtering
assuming a recessive pattern of inheritance, combined with the use of the C-score,
successfully narrowed down the candidates to compound heterozygous mutations in the
ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T
or p.P377L).
Conclusions
WES combined with integrated variant annotation prediction successfully identified
asymptomatic Tangier disease with novel ABCA1 mutations. This comprehensive approach
is useful to determine causative variants, especially in recessive inherited diseases.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: April 07, 2015
Accepted:
April 2,
2015
Received in revised form:
March 8,
2015
Received:
January 30,
2015
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
