Background: Exome sequencing has become more and more affordable and the technique has emerged as an important diagnostic tool for monogenic disorders at early stages of investigations, in particular when clinical information is limited or unspecific as well as in cases of genetic heterogeneity.
Methods: We identified a consanguineous Pakistani family segregating an autosomal recessive phenotype characterized by muscular hypertrophy, mild mental retardation and skeletal abnormalities. The available clinical information was incomplete and we applied whole exome sequencing in an affected family member for the identification of candidate gene variants.
Results: Exome sequencing identified a previously unreported homozygous mutation in the acceptor splice site of intron 5 in the BSCL2 gene (c.574-2A > G). Expression analysis revealed that the mutation was associated with skipping of exon 6. BSCL2 mutations are associated with Berardinelli-Seip congenital lipodystrophy and a clinical re-evaluation of affected individuals confirmed the diagnosis.
Conclusions: Exome sequencing is a powerful technique for the identification of candidate gene variants in Mendelian traits. We applied this technique on a single individual affected by a likely autosomal recessive disorder without access to complete clinical details. A homozygous and truncating mutation was identified in the BSCL2 gene suggesting congenital generalized lipodystrophy. Incomplete phenotypic delineations are frequent limiting factors in search for a diagnosis and may lead to inappropriate care and follow-up. Our study exemplifies exome sequencing as a powerful diagnostic tool in Mendelian disorders that may complement missing clinical information and accelerate clinical diagnosis.