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

Hum Genet. 2022 Apr;141(3-4):431-444. doi: 10.1007/s00439-022-02444-x.

Justin A Pater ¹ ², Cindy Penney ¹ ³, Darren D O'Rielly ¹ ³, Anne Griffin ¹, Lara Kamal ⁴, Zippora Brownstein ⁴, Barbara Vona ⁵ ⁶, Chana Vinkler ⁷, Mordechai Shohat ⁸ ⁹, Ortal Barel ⁸ ⁹, Curtis R French ¹, Sushma Singh ¹⁰, Salem Werdyani ¹, Taylor Burt ¹, Nelly Abdelfatah ¹, Jim Houston ¹, Lance P Doucette ¹, Jessica Squires ¹, Fabian Glaser ¹¹, Nicole M Roslin ¹², Daniel Vincent ¹³, Pascale Marquis ¹⁴, Geoffrey Woodland ¹, Touati Benoukraf ¹, Alexia Hawkey-Noble ¹, Karen B Avraham ⁴, Susan G Stanton ^# ¹⁰, Terry-Lynn Young ^# ¹⁵ ¹⁶ ¹⁷

Affiliations

1 Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada.
2 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
3 Centre for Translational Genomics, Memorial University, 300 Prince Phillip Dr., St. John's, NL, Canada.
4 Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 6997801, Tel Aviv, Israel.
5 Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
6 Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
7 Institute of Medical Genetics, Wolfson Medical Center, 58100, Holon, Israel.
8 Bioinformatic Center, Cancer Research Institute, The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
9 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
10 Communication Sciences and Disorders, Elborn College, Western University, 1201 Western Road, London, ON, Canada.
11 The Lorry I. Lokey Center for Life Sciences and Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
12 The Centre for Applied Genomics, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON, Canada.
13 Genome Quebec Innovation Centre, McGill University, 740 Dr. Penfield Avenue, Montreal, QC, Canada.
14 Canadian Centre for Computational Genomics, McGill University and Genome Quebec Innovation Center, 740 Dr. Penfield Avenue, Montreal, QC, Canada.
15 Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada. [email protected].
16 Centre for Translational Genomics, Memorial University, 300 Prince Phillip Dr., St. John's, NL, Canada. [email protected].
17 Communication Sciences and Disorders, Elborn College, Western University, 1201 Western Road, London, ON, Canada. [email protected].
# Contributed equally.

PMID: 35278131 DOI: 10.1007/s00439-022-02444-x

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.

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