Table 1.
Novel and reported variants in this study of genes known to be associated with autosomal recessive hearing loss.
| Family | Gene | Variant | Protein change | Reference | Allele frequency | ||
|---|---|---|---|---|---|---|---|
| Pakistan | 1000G | ExAC | |||||
| PKDF1551 | ADGRV1 | c.1055C>T | p.(Pro352Leu) | This study | - | - | 2.5E-05 |
| DEM4304, DEM4384, DEM4558, DEM4150, DEM4576, DEM4592, DEM4593, PKDF970b, PKDF1673, PKSR20 | BSND | c.35T>C | p.(Ile12Thr) | Riazuddin et al., 2009 | - | - | 2E-05 |
| DEM4545 | CABP2 | c.637+1G>T | Splice error | Schrauwen et al., 2012 | - | 0.0008 | 0.001 |
| PKDF1767 | CDH23† | c.2866G>A | p.(Glu956Lys) | Miyagawa, Naito, Nishio, Kamatani, & Usami, 2013 | - | - | - |
| PKDF055 | CDH23† | c.2968G>A | p.(Asp990Asn) | Bork et al., 2001 | - | - | - |
| DEM4556 | CDH23† | c.3481C>T | p.(Arg1161*) | Roux et al., 2006 | - | - | - |
| DEM4504 | CDH23† | c.3880C>T | p.(Gln1294*) | Bork et al., 2001 | - | - | - |
| DEM4324 | CDH23† | c.4892C>T | p.(Ala1631Val) | Shearer et al., 2013 | 0/188 | 0.0010 | 0.0009 |
| DEM4108 | CDH23† | c.5149T>C | p.(Cys1717Arg) | Sloan-Heggen et al., 2015 | 0/188 | - | 8.E-06 |
| PKDF055 | CDH23† | c.6049+1G>A | Splice error | Bork et al., 2001 | - | - | - |
| DEM4363 | CDH23† | c.6050–9G>A | Splice error | von Brederlow et al., 2002 | - | - | - |
| LUAB14 | CDH23† | c.6083A>C | p.(Asp2028Ala) | This study | 0/100 | - | - |
| DEM4112, PKDF1781 | CDH23† | c.6133G>A | p.(Asp2045Asn) | Bork et al., 2001 | - | - | 8E-06 |
| DEM4544 | CDH23† | c.6202A>C | p.(Thr2068Pro) | This study | 0/202 | - | 8E-06 |
| DEM4710 | CDH23† | c.6604G>A | p.(Asp2202Asn) | Bork et al., 2001 | - | - | 8E-06 |
| HL007 | CDH23† | c.7814A>G | p.(Asn2605Ser) | Naz et al., 2017 | 0/125 | - | - |
| DEM4491 | CDH23† | c.7987_7989delTTC | p.(Phe2664del) | Schultz et al., 2011 | 0/188 | - | - |
| DEM4305 | CDH23† | c.8351_8352insCGAT | p.(Leu2785Aspfs*43) | This study | 0/284 | - | - |
| DEM4042, DEM4053, DEM4630, DEM4722, DEM4749, DEM4785, DEM4789, DEM4791, DEM4793, DEM4868, DEM4870, PKDF1093, PKDF1285, PKDF520, PKDF781 | CIB2† | c.272T>C | p.(Phe91Ser) | Riazuddin et al., 2012 | - | - | 5E-05 |
| PKZA13 | CIB2† | c.297C>G | p.(Cys99Trp) | Riazuddin et al., 2012 | - | - | - |
| DEM4312 | CLCNKA | c.1985G>T | p.(Gly662Val) | This study | 0/198 | - | - |
| DEM4101, DEM4210, PKDF958, PKDF1660 | CLDN14† | c.254T>A | p.(Val85Asp) | Lee, Ansar, et al., 2012 | - | - | 8E-06 |
| DEM4005 | EDNRB | c.553G>A | p.(Val185Met) | Puffenberger et al., 1994 | - | - | 0.0001 |
| DEM4134 | EPS8 | c.205–8A>G | Splice error | This study | - | - | - |
| PKDF1550 | ESPN† | c.2496_2496delC | p.(Tyr832*) | This study | - | - | 8.4E-06 |
| DEM4704 | ESRRB† | c.536G>A | p.(Arg179His) | Miyagawa et al., 2013 | - | - | 2E-05 |
| PKDF969, PKDF1442, PKDF1573 | GIPC3† | c.662C>T | p.(Thr221Ile) | Rehman et al., 2011 | - | - | 4E-05 |
| DEM4551B, DEM4582 | GJB2 | c.−23+1G>A | Splice error | Denoyelle et al., 1997 | - | - | - |
| DEM4347, DEM4648, DEM4659, DEM4352A, DEM4871, PKSR8a, PKDF1621 | GJB2 | c.35delG | p.(Gly12Valfs*2) | Zelante et al., 1997 | - | 0.002 | 0.006 |
| DEM4307, DEM4339, DEM4346, DEM4351, DEM4409, DEM4550, DEM4573, DEM4582, DEM4583, DEM4656, DEM4717, DEM4438A, DEM4866, DEM4981, PKDF021, PKDF936, PKDF939, PKDF1368, PKDF1553, PKDF1655, PKDF1760 | GJB2 | c.71G>A | p.(Trp24*) | Kelsell et al., 1997; Santos, Wajid, Pham, et al., 2005 | - | 0.0004 | 0.0006 |
| PKDF1666 | GJB2 | c.223C>T | p.(Arg75Trp) | Richard et al., 1998 | - | - | - |
| DEM4528, DEM4537 | GJB2 | c.224G>A | p.(Arg75Gln) | Uyguner et al., 2002 | - | - | - |
| DEM4015A, DEM4143, DEM4255, DEM4262, DEM4479, DEM4660, DEM4670, DEM4696, DEM4737, DEM4769, DEM4770, DEM4972, PKDF936, PKDF1588, PKDF1633, PKDF1665, PKDF1675, PKDF1790 | GJB2 | c.231G>A | p.(Trp77*) | Santos, Wajid, Pham, et al., 2005 | - | - | 0.0001 |
| DEM4614 | GJB2 | c.355G>T | p.(Glu119*) | This study | 0/454 | - | 7E-05 |
| PKDF1694, PKDF1764 | GJB2 | c.457G>A | p.(Val153Ile) | Marlin et al., 2001 | - | - | - |
| DEM4431, DEM4653 | GPSM2 | c.138C>A | p.(Phe46Leu) | This study | 0/328 | - | 8E-06 |
| PKDF1679 | GRXCR1† | c.229C>T | p.(Gln77*) | Schraders et al., 2010 | - | - | - |
| DEM4153 | GRXCR1† | c.655G>A | p.(Glu219Lys) | This study | 0/114 | - | - |
| DEM4494, DEM4521, DEM4522, DEM4562, DEM4564, DEM4586, DEM4622, DEM4628, DEM4642, DEM4665, DEM4701, DEM4865, DEM4861, DEM4880, DEM4925, DEM4943, PKDF970a, PKDF1017, PKDF1331, PKDF1579, PKDF1604, PKDF1637, PKDF1668, PKDF1754, PKDF1787, PKDF1791 | HGF† | c.482 +1986_88delTGA | Schultz et al., 2009 | - | - | - | |
| PKDF1775 | HGF† | c.482 +1991_2000delGATGATGAAA | Schultz et al., 2009 | - | - | - | |
| PKDF1651 | ILDR1 | c.3G>A | p.(Met1Ile) | Borck et al., 2011 | - | - | - |
| DEM4175 | ILDR1 | c.900delG | p.(Thr301Profs*20) | This study | 0/188 | - | - |
| PKDF1455 | ILDR1 | c.1005_1005delG | p.(Glu335Aspfs*30)) | This study | - | - | - |
| DEM4353 | ILDR1 | c.1029_1030delTT | p.(Trp344Glyfs*17) | This study | 0/282 | - | - |
| PKDF1428 | ILDR1 | c.1384C>T | p.(Arg462*) | This study | - | - | 6E-05 |
| PKDF1311, PKDF1549 | LHFPL5† | c.250delC | p.(Leu84*) | Shabbir et al., 2006 | - | - | - |
| PKDF1178 | LHFPL5† | c.452 G>T | p.(Gly151Val) | This study | - | - | 8.00E-06 |
| PKDF1662 | MARVELD2† | c.1138C>T | p.(Gln380*) | Sloan-Heggen et al., 2015 | - | - | - |
| DEM4204 | MARVELD2† | c.1223_1224insA | p.(Glu408Argfs*4) | This study | 0/280 | - | - |
| DEM4393, DEM4533, PKDF1639, PKDF1641 | MARVELD2† | c.1295+2T>C | Splice error | Riazuddin et al., 2006 | - | - | 4E-05 |
| PKDF1111, PKDF1489, PKDF1606, PKDF1610, PKDF1727 | MSRB3† | c.265T>G | p.(Cys89Gly) | Ahmed et al., 2011 | - | - | 2E-05 |
| PKDF1789 | MSRB3† | c.412–1G>A | Splice error | This study | - | - | 8.2E-06 |
| PKDF019A | MYO7A | c.20G>T | p.(Gly7Val) | This study | 0/170 | - | 1E-05 |
| PKDF173 | MYO7A | c.93C>A | p.(Cys31*) | Weston et al., 1996 | - | 0.017 | 5E-05 |
| DEM4493 | MYO7A | c.247C>A | p.(Arg83Ser) | This study | 0/112 | - | - |
| PKDF312 | MYO7A | c.397dupC | p.(His133Profs*7) | Riazuddin et al., 2008 | - | - | 0.0006 |
| PKDF1465, PKDF1490 | MYO7A | c.496delG | p.(Glu166Argfs*5) | Riazuddin et al., 2008 | - | - | - |
| DEM4141, DEM4299, DEM4365 | MYO7A | c.722G>A | p.(Arg241His) | Cremers et al., 2007 | - | 0.0002 | 2E-05 |
| PKDF370 | MYO7A | c.977T>A | p.(Leu326Gln) | Riazuddin et al., 2008 | - | - | - |
| PKDF537, PKDF1786 | MYO7A | c.1183C>T | p.(Arg395Cys) | Shahzad et al., 2013 | 0/176 | - | - |
| DEM4190, DEM4652 | MYO7A | c.1258A>T | p.(Lys420*) | Le Quesne Stabej et al., 2012 | - | - | 4E-05 |
| DEM4331 | MYO7A | c.1591C>T | p.(Gln531*) | Riazuddin et al., 2008 | - | - | 8E-06 |
| PKDF019A | MYO7A | c.1849T>C | p.(Ser617Pro) | Carss et al., 2017 | 0/160 | - | 5E-05 |
| PKDF721 | MYO7A | c.2339delG | p.(Gly780Valfs*10) | This study | 0/154 | - | - |
| PKDF312 | MYO7A | c.3136dupC | p.(Leu1046Profs*9) | Riazuddin et al., 2008 | - | - | - |
| DEM4561 | MYO7A | c.3364C>A | p.(Leu1122Ile) | This study | - | - | - |
| DEM4281, DEM4692, PKDF628 | MYO7A | c.3502C>T | p.(Arg1168Trp) | Le Guedard-Mereuze et al., 2010 | - | 0.0002 | 0.0001 |
| PKDF1484 | MYO7A | c.3508G>A | p.(Glu1170Lys) | Riazuddin et al., 2008 | - | - | - |
| DEM4052A | MYO7A | c.3590T>C | p.(Leu1197Pro) | This study | 0/282 | - | - |
| PKDF173 | MYO7A | c.3728C>G | p.(Pro1243Arg) | This study | 0/164 | - | - |
| DEM4652 | MYO7A | c.4505A>G | p.(Asp1502Gly) | This study | 0/454 | - | 2E-05 |
| DEM4182, DEM4190, DEM4281, DEM4513, DEM4692, DEM4694 | MYO7A | c.4838delA | p.(Asp1613Valfs*32) | Riazuddin et al., 2008 | - | - | - |
| DEM4433 | MYO7A | c.5326+3A>G | Splice error | This study | 0/118 | - | - |
| DEM4561 | MYO7A | c.5345G>C | p.(Gly1782Ala) | This study | - | - | 4E-05 |
| DEM4206 | MYO7A | c.5434G>A | p.(Glu1812Lys) | Roux et al., 2006 | - | - | - |
| DEM4327 | MYO7A | c.5522C>G | p.(Thr1841Arg) | This study | 0/178 | - | - |
| DEM4725 | MYO7A | c.5660C>T | p.(Pro1887Leu) | Ben-Salem et al., 2014; Bharadwaj, Kasztejna, Huq, Berson, & Dryja, 2000 | - | - | 2E-05 |
| PKDF974 | MYO7A | c.5856+5G>C | Splice error | This study | 0/148 | - | - |
| PKDF1382 | MYO15A | c.2456C>A | p.(Ser819*) | Naz et al., 2017 | - | - | - |
| PKDF1657 | MYO15A | c.3843C>T | p.(Arg1169*) | This study | - | - | 8E-06 |
| PKDF1693 | MYO15A | c.4528C>T | p.(Gln1510*) | Rehman, et al., 2016 | - | - | 8E-06 |
| PKDF1693 | MYO15A | c.4570C>T | p.(Gln1524*) | This study | - | - | - |
| PKDF1780 | MYO15A | c.3505C>T | p.(Gln1669*) | This study | - | - | - |
| PKDF016 | MYO15A | c.8224+3A>G | Splice error | Rehman et al., 2016 | - | - | - |
| DEM4725 | OTOA | c.1148C>T | p.(Ala383Val) | EVS variant | - | - | 8E-04 |
| PKDF889 | OTOA | c.1352G>A | p.(Gly451Asp) | Lee et al., 2013 | - | - | 8E-06 |
| DEM4362, DEM4366 | OTOF | c.1550T>C | p.(Leu517Pro) | This study | 0/188 | - | - |
| PKDF1723 | OTOF | c.1904T>A | p.(Val635Asp) | This study | - | - | - |
| PKDF1535 | OTOF | c.2122C>T | p.(Arg708*) | Choi et al., 2009 | - | - | - |
| DEM4078 | OTOF | c.2508C>A | p.(Tyr836*) | Choi et al., 2009 | - | - | 0.0006 |
| DEM4512 | OTOF | c.2896G>A | p.(Glu966Lys) | Choi et al., 2009 | - | - | 8E-06 |
| DEM4548 | OTOF | c.2965_2967delTTC | p.(Phe989del) | Naz et al., 2017 | 0/188 | - | - |
| DEM4756 | OTOF | c.3376dupA | p.(Ile1126Asnfs*5 | This study | - | - | - |
| PKDF1336 | OTOF | c.3514C>T | p.(Arg1172Trp) | This study | - | 0.0002 | 2.7E-05 |
| PKDF1450 | OTOF | c.4799+1G>A | Splice error | This study | - | - | 8.24e-06 |
| PKDF1066a | OTOF | c.5714G>T | p.(Gly1905Val) | This study | 0/168 | - | |
| DEM4372B | OTOG | c.7235delG | p.(Arg2412Hisfs*77) | This study | 1/326 | - | 0.0009 |
| PKDF627 | PCDH15† | deletion of exons 14 and 15 | This study | 0/100 | - | - | |
| PKDF1440 | PCDH15† | c.400C>G | p.(Arg134Gly) | Ahmed et al., 2003 | - | - | - |
| PKDF1499 | PCDH15† | c.788C>A | p.(Pro263Gln) | This study | - | - | - |
| DEM4711 | PCDH15† | c.1737C>A | p.(Tyr584*) | Jaijo et al., 2006 | - | - | - |
| DEM4040 | PJVK | c.158C>G | p.(Ser53*) | This study | 0/284 | - | - |
| DEM4529 | PJVK | c.162_172del | p.(Pro55Glufs*23) | This study | 0/454 | - | - |
| DEM4752 | PJVK | c.406C>T | p.(Arg136*) | This study | - | - | - |
| PKDF880 | PJVK | c.908_910delACA | p.(Asn303del) | This study | 0/168 | - | - |
| PKDF908 | POU3F4 | c.478C>T | p.(Gln160*) | This study | 0/71 | - | - |
| PKDF1595 | POU4F3 | c.374C>T | p.(Pro125Leu) | This study | - | - | - |
| DEM4437 | PTPRQ | c.5158_5159delAT | p.(Ile1720Glnfs*7) | This study | 0/180 | - | - |
| DEM4123 | PTPRQ | c.6739–1G>A | Splice error | This study | 0/172 | - | - |
| DEM4465 | SLC26A4 | c.42delC | p.(Glu15Serfs*51) | This study | 0/454 | - | - |
| DEM4149B, HL005 | SLC26A4 | c.71G>T | p.(Arg24Leu) | Anwar et al., 2009 | - | - | 0.0003 |
| DEM4549 | SLC26A4 | c.154A>T | p.(Lys52*) | This study | 0/454 | - | - |
| DEM4511 | SLC26A4 | c.317C>T | p.(Ala106Val) | This study | 0/454 | - | - |
| DEM4014A | SLC26A4 | c.413T>A | p.(Val138Asp) | Chen, Wang, Sun, & Jiang, 2012 | |||
| DEM4436 | SLC26A4 | c.416G>T | p.(Gly139Val) | Anwar et al., 2009 | - | - | 4E-05 |
| DEM4092, DEM4149B, DEM4152, DEM4220, DEM4241, DEM4271, DEM4290, DEM4292, DEM4293, DEM4295, DEM4296, DEM4429, DEM4482, DEM4483, DEM4523, DEM4575, DEM4726, DEM4766, DEM4192, DEM4291, DEM4481, DEM4982, PKDF1161, PKDF1664 | SLC26A4 | c.716T>A | p.(Val239Asp) | Park et al., 2003 | - | 0.0002 | 0.0003 |
| DEM4186, DEM4454, DEM4455 | SLC26A4 | c.919–2A>G | Splice error | Coucke et al., 1999 | - | - | 0.0003 |
| DEM4336 | SLC26A4 | c.1001G>T | p.(Gly334Val) | Kahrizi et al., 2009 | - | - | 8E-06 |
| DEM4109 | SLC26A4 | c.1198delT | p.(Cys400Valfs*32) | Everett et al., 1997 | - | - | 2.00E-05 |
| PKDF384b | SLC26A4 | c.1226G>A | p.(Arg409His) | Van Hauwe et al., 1998 | - | - | 0.0001 |
| PKDF128, PKDF384b, PKDF910 | SLC26A4 | c.1226G>C | p.(Arg409Pro) | Park et al., 2003 | - | - | - |
| DEM4283, PKDF384b | SLC26A4 | c.1229C>T | p.(Thr410Met) | Coucke et al., 1999 | - | 0.0002 | 0.0002 |
| DEM4355 | SLC26A4 | c.1238A>G | p.(Gln413Arg) | Ji et al., 2009 | - | - | 8E-06 |
| DEM4200 | SLC26A4 | c.1264–3C>G | Splice error | This study | 0/454 | - | - |
| DEM4004, DEM4094A, DEM4220, DEM4276, DEM4574, DEM4695, DEM4702, DEM4966 | SLC26A4 | c.1337A>G | p.(Gln446Arg) | Reardon, CF, Trembath, Jan, & Phelps, 2000 | - | - | |
| DEM4286, DEM4287, DEM4294, DEM4392, DEM4425, DEM4553 | SLC26A4 | c.2106delG | p.(Lys702Asnfs*19) | Yazdanpanahi et al., 2012 | - | - | 8E-06 |
| PKDF1283 | TECTA | c.840_841insT | p.(Val281Cysfs*11) | This study | 0/162 | - | - |
| HL04 | TECTA | c.1247_1248delGG | p.(Gly416Aspfs*24) | This study | 0/100 | - | - |
| DEM4242A | TECTA | c.1774G>A | p.(Val592Met) | This study | 0/132 | - | - |
| PKDF1452 | TECTA | c.2736C>A | p.(Cys912*) | This study | - | - | - |
| PKDF1452 | TECTA | c.6162+5G>A | Splice error | This study | |||
| DEM4367, PKDF1584 | TMC1† | c.100C>T | p.(Arg34*) | Kurima et al., 2002 | - | - | - |
| PKSR39a | TMC1† | c.596A>T | p.(Asn199Ile) | Imtiaz et al., 2016 | 0/148 | - | 8E-06 |
| DEM4451 | TMC1† | c.945G>A | p.(Trp315*) | This study | 0/454 | - | - |
| DEM4396 | TMC1† | c.1114G>A | p.(Val372Met) | Santos, Wajid, Khan, et al., 2005 | - | - | 7E-05 |
| PKSR13b | TMC1† | c.1143C>G | p.(Tyr381*) | This study | 0/166 | - | - |
| DEM4147 | TMC1† | c.1209G>A | p.(Trp403*) | This study | - | - | - |
| DEM4132 | TMC1† | c.1224+2T>C | Splice error | This study | 0/112 | - | - |
| HL006 | TMC1† | c.1259G>A | p.(Cys420Tyr) | This study | 0/125 | - | - |
| PKDF025 | TMC1† | c.1333C>T | p.(Arg445Cys) | Sirmaci et al., 2009 | - | - | - |
| DEM4325 | TMC1† | c.1363T>C | p.(Tyr454His) | NSHI | - | - | - |
| PKDF1449 | TMC1† | c.1543C>T | p.(Cys515Arg) | Kitajiri et al., 2007 | - | - | - |
| DEM4350 | TMC1† | c.1728C>G | p.(Asn576Lys) | This study | 0/454 | - | - |
| PKDF1617 | TMC1† | c. 1753_1754insA | p.(Asn407Lysfs*2) | This study | - | - | - |
| HL006 | TMC1† | c.1788C>A | p.(Ser596Arg) | Imtiaz et al., 2016 | 0/125 | - | - |
| PKSR13b | TMC1† | c.1810C>T | p.(Arg604*) | Sirmaci et al., 2009 | 8E-06 | - | - |
| DEM4370A, DEM4724 | TMC1† | c.2035G>A | p.(Glu679Lys) | Santos, Wajid, Khan, et al., 2005 | - | - | - |
| DEM4486 | TMIE† | c.241C>T | p.(Arg81Cys) | Santos et al., 2006 | - | - | - |
| DEM4687 | TMIE† | c.250C>T | p.(Arg84Trp) | Naz et al., 2002 | - | - | 2E-05 |
| DEM4020, PKDF1053 | TMPRSS3† | c.271C>T | p.(Arg91*) | Bademci et al., 2016 | - | - | 2E-05 |
| DEM4003 | TMPRSS3† | c.323–6G>A | Splice error | Scott et al., 2001 | - | - | 6E-05 |
| PKSR31 | TMPRSS3† | c.581G>T | p.(Cys194Phe) | Ben-Yosef et al., 2001 | - | - | - |
| DEM4106, DEM4124 | TMPRSS3† | c.767C>T | p.(Ala256Val) | Lee, Khan, et al., 2012 | - | - | - |
| PKDF765 | TMPRSS3† | c.783–1G>T | Splice error | This study | 0/130 | - | |
| DEM4046, DEM4202, DEM4372A, DEM4560, LUAB13, HL003, PKDF1057, PKDF1330, PKDF1634 | TMPRSS3† | c.1219T>C | p.(Cys407Arg) | Ben-Yosef et al., 2001 | - | - | 5E-05 |
| HL007, PKDF1756, PKDF1757, PKDF1758 | TPRN† | c.1056G>A | p.(Trp352*) | Rehman et al., 2010 | - | - | - |
| DEM4492 | TRIOBP† | c.3460_3461delCT | p.(Leu1154Alafs*29) | This study | 0/454 | - | - |
| PKDF1430 | TRIOBP† | c.3634_3646delCTGATCCCCCAAG | p.(Leu1212Cysfs*22) | This study | - | - | - |
| DEM4707 | USH1C | c.238dup | p.(Arg80Profs*69) | Bitner-Glindzicz et al., 2000 | - | - | 0.0003 |
| DEM4335B | USH1C | c.463C>T | p.(Arg155*) | Ebermann et al., 2007 | - | - | 8E-06 |
| DEM4675 | USH1G | c.511G>T | p.(Glu171*) | This study | - | 0.0002 | 2E-05 |
| DEM4268 | USH1G | c.812delC | p.(Pro271Argfs*52) | This study | 0/454 | - | - |
| DEM4689 | USH2A | c.3661C>T | p.(Gln1221*) | This study | 0/134 | - | 8E-06 |
| DEM4171 | WHRN | c.2388_2389delCG | p.(Asn796Lysfs*46) | This study | 0/284 | ||
Novel mutations from this study are in bold font.
(†)
indicates genes associated with non-syndromic autosomal recessive hearing loss that were discovered through studies in Pakistani pedigrees.
Pak: Pakistani controls, 1000G: 1000 Genomes Project database, ExAc: Exome Aggregation Consortium database.
(-)
indicates that the variant is absent from the respective database.