Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene

Justin A. Pater, Cindy Penney, Darren D. O’Rielly, Anne Griffin, Lara Kamal, Zippora Brownstein, Barbara Vona, Chana Vinkler, Mordechai Shohat, Ortal Barel, Curtis R. French, Sushma Singh, Salem Werdyani, Taylor Burt, Nelly Abdelfatah, Jim Houston, Lance P. Doucette, Jessica Squires, Fabian Glaser, Nicole M. RoslinDaniel Vincent, Pascale Marquis, Geoffrey Woodland, Touati Benoukraf, Alexia Hawkey-Noble, Karen B. Avraham, Susan G. Stanton, Terry Lynn Young*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing 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: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3′ UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). 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.

Original languageEnglish
Pages (from-to)431-444
Number of pages14
JournalHuman Genetics
Volume141
Issue number3-4
DOIs
StatePublished - Apr 2022

Funding

FundersFunder number
Government of Newfoundland and Labrador
Janeway Children?s Hospital Foundation
Janeway Children’s Hospital Foundation
Memorial University
National Institutes of Health
National Institute on Deafness and Other Communication DisordersR01DC011835
National Institute on Deafness and Other Communication Disorders
Genome Canada
Canadian Institutes of Health Research
Canada Foundation for Innovation13120, 9384
Canada Foundation for Innovation
Deutsche Forschungsgemeinschaft

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