2. Academic Validation
  3. Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma

Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma

  • Eur J Hum Genet. 2019 Jun;27(6):869-878. doi: 10.1038/s41431-019-0372-y.
Isabelle Schrauwen 1,  Béla I Melegh 2,  Imen Chakchouk 1,  Anushree Acharya 1,  Abdul Nasir 3,  Alexis Poston 1,  Diana M Cornejo-Sanchez 1 4,  Zsolt Szabo 5,  Tamás Karosi 5,  Judit Bene 2,  Béla Melegh 2,  Suzanne M Leal 6
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 2 Department of Medical Genetics, University of Pecs, Medical School, and Szentagothai Research Centre, Pecs, Hungary.
  • 3 Synthetic Protein Engineering Lab (SPEL), Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, South Korea.
  • 4 Grupo Mapeo Genético, Facultad de Medicina, Universidad de Antioquia. Medellín, 050010470, Antioquia, Colombia.
  • 5 Department of Otolaryngology and Head and Neck Surgery, B-A-Z County Central Hospital and University Teaching Hospital, Miskolc, Hungary.
  • 6 Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, USA. [email protected].
PMID: 30872814 DOI: 10.1038/s41431-019-0372-y
Abstract

Roma are a socially and culturally distinct isolated population with genetically divergent subisolates, residing mainly across Central, Southern, and Eastern Europe. We evaluated the genetic etiology of hearing impairment (HI) in 15 Hungarian Roma families through exome sequencing. A family with autosomal dominant non-syndromic HI segregating a rare variant in the Calponin-homology 2 domain of PLS1, or Plastin 1 [p.(Leu363Phe)] was identified. Young adult Pls1 knockout mice have progressive HI and show morphological defects to their inner hair cells. There is evidence that PLS1 is important in the preservation of adult stereocilia and normal hearing. Four families segregated the European ancestral variant c.35delG [p.(Gly12fs)] in GJB2, and one family was homozygous for p.(Trp24*), an Indian subcontinent ancestral variant which is common amongst Roma from Slovakia, Czech Republic, and Spain. We also observed variants in known HI genes USH1G, USH2A, MYH9, MYO7A, and a splice site variant in MANBA (c.2158-2A>G) in a family with HI, intellectual disability, behavioral problems, and respiratory inflammation, which was previously reported in a Czech Roma family with similar features. Lastly, using multidimensional scaling and ADMIXTURE analyses, we delineate the degree of Asian/European admixture in the HI families understudy, and show that Roma individuals carrying the GJB2 p.(Trp24*) and MANBA c.2158-2A>G variants have a more pronounced South Asian background, whereas the other hearing-impaired Roma display an ancestral background similar to Europeans. We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI.

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