Discovery of a novel cystathionine-beta-synthase mutation and diagnosis of homocystinuria by whole exome sequencing in a family from rural Honduras

Objective: Lack of newborn screening, limited access to healthcare, and complex presentation has resulted in gross under-diagnosis of in-born metabolism disorders in many Central American countries. In this study we describe the use of advanced clinical genomics to identify a novel cystathionine-beta-synthase (CBS) mutation with limited clinical information from a small highly consanguineous indigenous community in rural Honduras. Methods: We performed chromosomal microarray analysis and whole exome sequencing on three affected siblings and their mother. Confirmatory Sanger sequencing for CBS exon 10 was performed on genomic DNA from extended family within the community. Results: We identified a novel homozygous missense mutation (p.Tyr308Thrfs*11) in CBS that resulted in the diagnosis of homocystinuria in three siblings. Patients were nonresponsive to standard pyridoxine treatment. We discovered an elevated coefficient of inbreeding (F ≥ 0.20) suggestive of an unreported highly consanguineous population. Genotyping identified ~47% of extended family as carriers of this novel mutation. Conclusion: Expanded use of whole exome sequencing from buccal cell genomic DNA allowed for the discovery of a novel mutation resulting in a rare recessive disorder in an isolated under-served population. Clinical phenotypes and treatment response of patients with this novel homozygous mutation add to our clinical understanding of homocystinuria.