Abstract
Background Bardet-Biedl syndrome (BBS) is
a pleiotropic recessive disorder that belongs to the
rapidly growing family of ciliopathies. It shares
phenotypic traits with other ciliopathies, such as Alstro
¨
m
syndrome (ALMS), nephronophthisis (NPHP) or Joubert
syndrome. BBS mutations have been detected in 16
different genes (BBS1-BBS16) without clear genotypeto-phenotype
correlation. This extensive genetic
heterogeneity is a major concern for molecular diagnosis
and genetic counselling. While various strategies have
been recently proposed to optimise mutation detection,
they either fail to detect mutations in a majority of
patients or are time consuming and costly.
Method We tested a targeted exon-capture strategy
coupled with multiplexing and high-throughput
sequencing on 52 patients: 14 with known mutations as
proof-of-principle and 38 with no previously detected
mutation. Thirty genes were targeted in total including
the 16 BBS genes, the 12 known NPHP genes, the single
ALMS gene ALMS1 and the proposed modifier
CCDC28B.
Results This strategy allowed the reliable detection of
causative mutations (including homozygous/
heterozygous exon deletions) in 68% of BBS patients
without previous molecular diagnosis and in all proof-ofprinciple
samples. Three probands carried homozygous
truncating mutations in ALMS1 confirming the major
phenotypic overlap between both disorders. The
efficiency of detecting mutations in patients was
positively correlated with their compliance with the
classical BBS phenotype (mutations were identified in
81% of ‘classical’ BBS patients) suggesting that only
a few true BBS genes remain to be identified. We
illustrate some interpretation problems encountered due
to the multiplicity of identified variants.
Conclusion This strategy is highly efficient and cost
effective for diseases with high genetic heterogeneity,
and guarantees a quality of coverage in coding
sequences of target genes suited for diagnosis purposes.
Lingua originale | English |
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pagine (da-a) | 502-512 |
Numero di pagine | 11 |
Rivista | JOURNAL OF MEDICAL GENETICS |
Volume | 2012 |
Stato di pubblicazione | Pubblicato - 2012 |
Keywords
- Bardet-Biedl syndrome
- high-throughput sequencing