Autosomal Dominant Non-Syndromic Hearing Loss Maps to DFNA33 (13q34) and Co-Segregates with Splice Site Variants in ATP11A, A Phospholipid Flippase Gene

Whole genome approaches are superior for identifying recessive genes, however discovery of dominant genes including deafness genes (DFNA) remains challenging. Herein we report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Targeted screening of DFNA genes based on audioprofiles was unsuccessful. Genome-wide SNP genotyping linked SNHL to DFNA33 (Lod = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL in 2009. WGS identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 Kb, excluding all but one variant. ATP11A (NC_000013.11: g.190616G > A) is a novel point mutation predicted to be a cryptic donor splice site. RNA studies in patient-derived tissues verified in silico predictions, revealing the retention of 153bp of intron in the 3’ UTR of several ATP11A isoforms. A second, unresolved family from Israel with a similar, variable form of SNHL and a novel duplication in exon 28 of ATP11A that occurs within the splice donor sequence (intron 28). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.