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Further Confirmation of the Association of SLC12A2 with Non-Syndromic

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Further Confirmation of the Association of SLC12A2 with Non-Syndromic www.nature.com/jhg ARTICLE OPEN Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment Samuel M. Adadey1,2,9, Isabelle Schrauwen3,9, Elvis Twumasi Aboagye1, Thashi Bharadwaj3, Kevin K. Esoh 2, Sulman Basit 4, 3 3 5 2 6 1 Anushree Acharya , Liz M. Nouel-Saied ,✉ Khurram Liaqat , Edmond✉ Wonkam-Tingang , Shaheen Mowla , Gordon A. Awandare , Wasim Ahmad 7, Suzanne M. Leal 3,8 and Ambroise Wonkam 2 © The Author(s) 2021 Congenital hearing impairment (HI) is genetically heterogeneous making its genetic diagnosis challenging. Investigation of novel HI genes and variants will enhance our understanding of the molecular mechanisms and to aid genetic diagnosis. We performed exome sequencing and analysis using DNA samples from affected members of two large families from Ghana and Pakistan, segregating autosomal-dominant (AD) non-syndromic HI (NSHI). Using in silico approaches, we modeled and evaluated the effect of the likely pathogenic variants on protein structure and function. We identified two likely pathogenic variants in SLC12A2, c.2935G>A:p.(E979K) and c.2939A>T:p.(E980V), which segregate with NSHI in a Ghanaian and Pakistani family, respectively. SLC12A2 encodes an ion transporter crucial in the homeostasis of the inner ear endolymph and has recently been reported to be implicated in syndromic and non-syndromic HI. Both variants were mapped to alternatively spliced exon 21 of the SLC12A2 gene. Exon 21 encodes for 17 residues in the cytoplasmatic tail of SLC12A2, is highly conserved between species, and preferentially expressed in cochlear tissues. A review of previous studies and our current data showed that out of ten families with either AD non-syndromic or syndromic HI, eight (80%) had variants within the 17 amino acid residue region of exon 21 (48 bp), suggesting that this alternate domain is critical to the transporter activity in the inner ear. The genotypic spectrum of SLC12A2 was expanded and the involvement of SLC12A2 in ADNSHI was confirmed. These results also demonstrate the role that SLC12A2 plays in ADNSHI in diverse populations including sub-Saharan Africans. Journal of Human Genetics; https://doi.org/10.1038/s10038-021-00954-6 INTRODUCTION the other Pakistani, both segregating autosomal-dominant (AD) Hearing impairment (HI) is the most common sensory human NSHI. The SLC12A are transmembrane proteins that mediate electro- disorder [1]. Although the characterization of HI is complex, it may neutral transport of ions, thus influx and efflux of Na+,K+,andCl− be described as conductive, sensorineural, or mixed; syndromic or ions [8]. They regulate physiological function, including ion non-syndromic (NS); prelingual or post-lingual, progressive, or transport, modulate inhibitory synaptic transmission, and maintain nonprogressive [2]. The etiology of HI stems from environmental and regulate cell volume [9]. (birth complications, some infectious diseases, chronic ear infections, ototoxic medications, accidents, exposure to excessive noise, and aging) and genetic/inheritable factors [1]. HI genetics is MATERIALS AND METHODS highly heterogeneous [2]; to date, >120 genes have been Participants’ enrollment implicated in NSHI [3]. Pathogenic variants in the gap junction Two families that reported congenital HI were recruited from Ghana (GH- protein beta 2 (GJB2), encoding for connexin 26, remain the most F4) and Pakistan (PK-4543; Fig. 1A, C). The Ghanaian family (GH-F4) common genetic cause of NSHI [4]. participated in a previous study that screened hearing-impaired families GJB2 The advancements in next-generation sequencing techniques from Ghana for mutations [10]. A structured questionnaire and a – review of the medical records of the participant were employed to rule out have accelerated the discovery of HI-associated gene variants [5 7]. environmental or syndromic HI and pure-tone audiometry was performed. In this report, we used exome sequencing (ES) to identify Pakistani family (PK-4543) is from the Mardan district in the Khyber pathogenic variants in SLC12A2 in two families, one Ghanaian and Pakhtunkhwa province of Pakistan. The patient evaluation included a 1West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana. 2Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. 3Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Centre, New York, NY, USA. 4Center for Genetics and Inherited Diseases, Taibah University Al Madinah Al Munawarah, Al Munawarah, Saudi Arabia. 5Faculty of Biological Sciences, Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan. 6Division of Haematology, Faculty of Health Sciences, Department of Pathology, University of Cape Town, Cape Town, South Africa. 7Faculty of Biological Sciences, Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan. 8Taub Institute for Alzheimer’s Disease and the ✉ Aging Brain, Columbia University Medical Centre, New York, NY, USA. 9These authors contributed equally: Samuel M. Adadey, Isabelle Schrauwen email: [email protected]. edu; [email protected] Received: 17 February 2021 Revised: 8 June 2021 Accepted: 20 June 2021 S.M. Adadey et al. 2 1234567890();,: Fig. 1 Pedigree and pure-tone audiometry measurements of affected families. A Pedigree and B audiograms of some individuals in the Ghanaian family (GH-F4), which segregates the SLC12A2: c.2935G>A: p.(E979K) variant. The ages of affected individuals: II:2, III:1, and III:5 in Fam GH-F4 at the time of sample collection were 29, 10, and 3 years, respectively. C Pedigree and D audiograms of some individuals in the Pakistan family (PK-4543) with SLC12A2: c.2939A>T: p.(E980V) variant. The ages of affected individuals in family PK-4543: II:3, II:5, III:2, III:4, III:5, IV:1, IV:2, and IV:3 at the time of sample collection were 56, 60, 38, 35, 37, 10, 11, and 13 years, respectively. The black shaded square and circles were used to denote hearing-impaired males and females, respectively. The unshaded squares and circles correspond to hearing males and females clinical history, physical, audiological, and vestibular examination, includ- Sample collection and initial screening ing pure-tone audiometry and a Romberg test. Environmental causes of HI, Peripheral blood samples were collected for genomic DNA (gDNA) such as maternal or perinatal infections, administration of ototoxic isolation for 4 family members (3 affected and 1 unaffected) from GH-F4 medications, or trauma were excluded. (I:2, II:2, III:1, and III:5) and for 12 family members (8 affected and 4 Journal of Human Genetics S.M. Adadey et al. 3 unaffected) from Pakistani pedigree PK-4543 (II:3, II:5, II:6, III:1–6, and familial history of congenital HI, following a likely AD inheritance, IV:1–3). gDNA isolation was performed using the QIAmp DNA Mixi Prep Kit from the maternal line (Fig. 1A). Pure-tone audiometry showed a and a phenol–chloroform protocol [11] for GH-F4 and PK-4543, respec- U-shaped bilateral severe-to-profound HI in affected family tively. Prior to exome sequencing, the entire coding region of GJB2 was members (Fig. 1B). Similarly, the mode of inheritance in the screened using Sanger sequencing in both families. Additional common Pakistani family was compatible with an AD mode of inheritance HI-associated variants in CIB2, HGF, and SLC26A4 in the Pakistani population were also screened via Sanger sequencing in family PK-4543, (Fig. 1C), with affected individuals displaying bilateral severe-to- as previously described [7]. profound HI (Fig. 1D), which was congenital and nonprogressive. Affected individuals in both Ghanaian and Pakistanis families did not have any additional phenotypic features. Exome sequencing Exome sequencing was performed on selected samples from each family (GH-F4: II:2, III:1, and III:5 and PK-4543: III:5 and IV:2). The gDNA samples Exome sequencing were fragmented and a library was prepared using the Illumina Nextera The average read depth was 80X and 65X for the Ghanaian and Rapid Capture Exome kit for family GH-F4 (37-Mb target region, Illumina, Pakistani samples, respectively. Filtering analysis of the families San Diego, CA, USA) and the SureSelect Human All Exon V6 kit for family identified heterozygous missense variants in exon 21 of SLC12A2 PK-4543 (60.5-Mb target region, Agilent Technologies, Santa Clara, CA, (OMIM:600840): NM_001046.2: c.2935G>A: p.(E979K) for family USA). Paired-end sequencing was performed on a HiSeq2500/4000 GH-F4 and c.2939A>T: p.(E980V) for family PK-4543. Each variant instrument (Illumina Inc, San Diego, CA, USA). was verified with Sanger sequencing (Fig. 2) and segregated with Reads were aligned to the human reference genome (GRCh37/Hg19) using the HI phenotype (Fig. S1A, B). Both variants are absent from – Burrows Wheeler Aligner-MEM for family PK-4543 [12]andtheDynamicRead gnomAD [16] and TopMed [23] databases. The variants were Analysis for GENomics (DRAGEN 05.021.408.3.4.12) software for GH-F4 (Illumina predicted to be deleterious by six bioinformatic tools and were Inc, San Diego, CA, USA). Duplicate removal, insertions/deletion (Indel)- fi fi realignment, and base quality score recalibration were performed with Picard- classi ed as likely pathogenic according to ACMG classi cation for tools and the Genome Analysis Toolkit (GATK) [13] (for PK-4543) and the HI (Table S1). DRAGEN software (for GH-F4). Single-nucleotide variantsandInDelswere The SLC12A2-c.2935G>A: p.(E979K) variant has previously been jointly called by the GATK HaplotypeCaller [13]. The sex of each individual with reported as a de novo variant in a Japanese patient with HI [24] exome data was verified using plinkv1.9 [14]. Familial relationships for and displayed AD inheritance in a family with HI and vestibular members with exome data were verified via Identity-by-Descent sharing areflexia of unknown ancestry [25]. Sanger sequencing confirmed (plinkv1.9) and the Kinship-based INference for Gwas algorithm [15].
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