This abstract was presented today at the Association for Research in Vision and Opthalmology (ARVO) meetings in Seattle, Washington by Lloyd B. Williams, Chad D. Huff, Denise Morgan, Rosann Robinson, Margaux Morrison, Krista Kinard, George Rodgers, Kathleen B. Digre, Kathleen and Margaret DeAngelis.
Purpose: Tantravahi et al. (2012) previously described a novel inherited syndrome consisting of a cone-rod dystrophy, chronic optic nerve edema and low-grade ocular inflammation, idiopathic massive splenomegaly, mild pancytopenia, and anhidrosis with unknown genetic mechanism. We conducted whole exome sequencing (WES) on DNA from the members of this pedigree to elucidate the genetic cause.
Methods: The three affected family members in this pedigree are: the proband and her mother and half-sister. All family members had extensive laboratory and clinical evaluations. DNA was collected from all affected individuals and from the following unaffected: both maternal grandparents, a maternal aunt, the proband’s father and her two full sisters. DNA from the proband, her affected mother, her unaffected father and one unaffected sister underwent WES. Target enrichment was performed with the Illumina TruSeq Exome Enrichment Kit followed by quantitative PCR (q-PCR) and sequencing via Illumina HiSeq2000 101 Cycle Paired End Sequencing. Analysis was performed using VAAST.
Results: VAAST identified 44 candidate variants. Sanger sequencing confirmed a missense mutation in ALPK1 segregating with disease. The mutation, chr4:113348736 C to T, results in a T237M amino acid change in the ALPK1 protein. Bioinformatic analysis predicts that this change is damaging to the protein and in a highly conserved region. ALPK1 mutation is the only candidate SNP that segregated with disease in the family. It was shown to be dominantly inherited and appeared de novo in the mother of the proband. ALPK1 has not been previously associated with retinal or ophthalmic disorders. There are no known similar cases elsewhere in the literature. The proband and her affected sister have different fathers. We, therefore, conclude that this is a dominantly inherited mutation that arose spontaneously in the mother of the proband.
Conclusions: The discovery of ALPK1 as the likely disease-causing mutation in this syndrome is a success in using WES to identify the genetic basis of a new ocular and systemic disorder. These data may yield new insights into function of the alpha protein kinase family of proteins, the molecular function of ALPK1 in photoreceptors, and a new type of genetic interaction between ocular and hematologic disorders.
A full size pdf of the poster can be downloaded here.