Knowledge base for genomic medicine in Japanese
掲載日: 2019/10/10更新日: 2022/10/18
遺伝性難聴
小児・神経疾患
MedGen ID
指定難病等
ガイドライン等
要注意の転帰
聴力消失の進行
検査の保険適用
あり
概念・疫学

先天性難聴は、新生児1,000人に1人の割合で発症する、先天性疾患の中で頻度が高い疾患の一つである。その原因は多岐にわたるが、最も高頻度に認められるのは遺伝子変異による遺伝性難聴によるもので、50%以上の症例に関与していると考えられている (Lancet. 2005. PMID: 15752533) 。遺伝形式から、常染色体優性遺伝形式、常染色体劣性遺伝形式、X連鎖遺伝形式、ミトコンドリア遺伝に分類されるが、70-80%は両親ともに難聴がなく、子どもに難聴が生じる常染色体劣性遺伝である。また、難聴の他に随伴症状を伴うか否かで、非症候性難聴 (外耳の目にみえる奇形や関連疾患がない場合) と症候性難聴 (外耳やその他の器官の奇形及びその他の臓器系の疾患を伴う場合) に分類される。非症候性難聴は遺伝性難聴の約70%を占め、残りの30%を占める症候性難聴には約400種類以上の疾患群が知られている。症候性難聴の多くは難聴以外の症状からも診断が可能であり、Alport症候群、branchio-oto-renal (BOR) 症候群、Jervell and Lange-Nielsen症候群、Norrie症候群、Pendred症候群、Stickler症候群、Treacher Collins症候群、User症候群、Waardenburg症候群などは各々原因遺伝子が特定されている。

遺伝性難聴は原因遺伝子によって、難聴の発症年齢、聴力レベル、聴力像、進行性の有無、随伴症状の有無、治療法の効果が異なることが明らかになってきている。それゆえ、遺伝学的検査によって難聴の正確な診断をつけることが重要であると考えられている。わが国では、信州大学が中心となって2008年7月に「先天性難聴の遺伝子診断」が先進医療として認められ、現在は保険診療で19遺伝子154変異の遺伝学的検査が実施できる。

予後

難聴を伴う遺伝性症候群が400以上報告されており、各疾患ごとに聴力低下の進行の程度は様々である。

治療

現時点では疾患そのものを治療する有効な治療法はなく、補聴器あるいは人工内耳による補聴が有用である。

Genes
Gene symbolOMIMSQM scoring*
Genomics England
PanelApp
PhenotypeVariant information
DIAPH1124900N/ADFNA1 (AD)https://omim.org/allelicVariants/602121
KCNQ4600101N/ADFNA2A (AD)https://omim.org/allelicVariants/603537
GJB3612644N/ADFNA2B (AD)https://omim.org/allelicVariants/603324
GJB2601544N/ADFNA3A (AD)https://omim.org/allelicVariants/121011
GJB6612643N/ADFNA3B (AD)https://omim.org/allelicVariants/604418
MYH14600652N/ADFNA4A (AD)https://omim.org/allelicVariants/608568
CEACAM16614614N/ADFNA4B (AD)https://omim.org/allelicVariants/614591
GSDME (DFNA5)600994N/ADFNA5 (AD)https://omim.org/allelicVariants/608798
WFS1600965N/ADFNA6/14/38 (AD)https://omim.org/allelicVariants/606201
LMX1A601412N/ADFNA7 (AD)https://omim.org/allelicVariants/600298
TECTA60154310NB (P)DFNA8/12 (AD)https://omim.org/allelicVariants/602574
COCH601369N/ADFNA9 (AD)https://omim.org/allelicVariants/603196
EYA4601316N/ADFNA10 (AD)https://omim.org/allelicVariants/603550
MYO7A601317N/ADFNA11 (AD)https://omim.org/allelicVariants/276903
COL11A2601868N/ADFNA13 (AD)https://omim.org/allelicVariants/120290
POU4F3602459N/ADFNA15 (AD)https://omim.org/allelicVariants/602460
MYH9603622N/ADFNA17 (AD)https://omim.org/allelicVariants/160775
ACTG1604717N/ADFNA20/26 (AD)https://omim.org/allelicVariants/102560
MYO660634610NB (P)DFNA22 (AD)https://omim.org/allelicVariants/600970
SIX1605192N/ADFNA23 (AD)https://omim.org/allelicVariants/601205
SLC17A8605583N/ADFNA25 (AD)https://omim.org/allelicVariants/607557
REST612431N/ADFNA27 (AD)https://omim.org/allelicVariants/600571
GRHL2608641N/ADFNA28 (AD)https://omim.org/allelicVariants/608576
NLRP3617772N/ADFNA34 (AD)https://omim.org/allelicVariants/606416
TMC1606705N/ADFNA36 (AD)https://omim.org/allelicVariants/606706
COL11A1618533N/ADFNA37 (AD)https://omim.org/allelicVariants/120280
DSPP605594N/ADFNA39, with dentinogenesis (AD)https://omim.org/allelicVariants/125485
CRYM616357N/ADFNA40 (AD)https://omim.org/allelicVariants/123740
P2RX2608224N/ADFNA41 (AD)https://omim.org/allelicVariants/600844
CCDC50607453N/ADFNA44 (AD)https://omim.org/allelicVariants/611051
MYO1A (DFNA48) 607841N/ADFNA48 (AD)N/A
MIR96613074N/ADFNA50 (AD)https://omim.org/allelicVariants/611606
TJP2 (DFNA51)613558N/ADFNA51 (AD)N/A
POU4F3 (DFNA52)607683N/ADFNA52 (AD)N/A
TNC615629N/ADFNA56 (AD)https://omim.org/allelicVariants/187380
DIABLO614152N/ADFNA64 (AD)https://omim.org/allelicVariants/605219
TBC1D24616044N/ADFNA65 (AD)https://omim.org/allelicVariants/613577
CD164616969N/ADFNA66 (AD)https://omim.org/allelicVariants/603356
OSBPL2616340N/ADFNA67 (AD)https://omim.org/allelicVariants/606731
HOMER2616707N/ADFNA68 (AD)https://omim.org/allelicVariants/604799
KITLG616697N/ADFNA69 (AD)https://omim.org/allelicVariants/184745
MCM2616968N/ADFNA70 (AD)https://omim.org/allelicVariants/116945
DMXL2617605N/ADFNA71 (AD)https://omim.org/allelicVariants/612186
SLC44A4617606N/ADFNA72 (AD)https://omim.org/allelicVariants/606107
PTPRQ617663N/ADFNA73 (AD)https://omim.org/allelicVariants/603317
PDE1C618140N/ADFNA74 (AD)https://omim.org/allelicVariants/602987
TRRAP618778N/ADFNA75 (AD)https://omim.org/allelicVariants/603015
PLS1618787N/ADFNA76 (AD)https://omim.org/allelicVariants/602734
ABCC1618915N/ADFNA77 (AD)https://omim.org/allelicVariants/158343
GJB222029010NB (P)DFNB1A (AR, DD)https://omim.org/allelicVariants/121011
GJB3220290N/ADeafness, digenic, GJB2/GJB3 (AR, DD)https://omim.org/allelicVariants/603324
GJB6220290N/ADeafness, digenic, GJB2/GJB6https://omim.org/allelicVariants/604418
GJB6612645N/ADFNB1B (AR)https://omim.org/allelicVariants/604418
MYO7A600060N/ADFNB2 (AR)https://omim.org/allelicVariants/276903
MYO15A60031610NB (P)DFNB3 (AR)https://omim.org/allelicVariants/602666
SLC26A4600791N/ADFNB4, with enlarged vestibular aqueduct (AR)https://omim.org/allelicVariants/605646
TMIE60097110NB (P)DFNB6 (AR)https://omim.org/allelicVariants/607237
TMC160097410NB (P)DFNB7 (AR)https://omim.org/allelicVariants/606706
TMPRSS3601072N/ADFNB8/10 (AR)https://omim.org/allelicVariants/605511
OTOF601071N/ADFNB9 (AR)https://omim.org/allelicVariants/603681
CDH2360138610NB (P)DFNB12 (AR)https://omim.org/allelicVariants/605516
ATP2B2601386N/ADFNB12, modifier of (AR)https://omim.org/allelicVariants/108733
GIPC360186910NB (P)DFNB15 (AR)https://omim.org/allelicVariants/608792
STRC60372010NB (P)DFNB16 (AR)https://omim.org/allelicVariants/606440
USH1C602092N/ADFNB18A (AR)https://omim.org/allelicVariants/605242
OTOG61494510NB (P)DFNB18B (AR)https://omim.org/allelicVariants/604487
TECTA60362910NB (P)DFNB21 (AR)https://omim.org/allelicVariants/602574
OTOA60703910NB (P)DFNB22 (AR)https://omim.org/allelicVariants/607038
PCDH15609533N/ADFNB23 (AR)https://omim.org/allelicVariants/605514
RDX61102210NB (P)DFNB24 (AR)https://omim.org/allelicVariants/179410
GRXCR161328510NB (P)DFNB25 (AR)https://omim.org/allelicVariants/613283
GAB1605428N/ADFNB26 (AR)https://omim.org/allelicVariants/604439
TRIOBP60982310NB (P)DFNB28 (AR)https://omim.org/allelicVariants/609761
CLDN1461403510NB (P)DFNB29 (AR)https://omim.org/allelicVariants/605608
MYO3A60710110NB (P)DFNB30 (AR)https://omim.org/allelicVariants/606808
WHRN607084N/ADFNB31 (AR)https://omim.org/allelicVariants/607928
CDC14A608653N/ADFNB32, with or without immotile sperm (AR)https://omim.org/allelicVariants/603504
ESRRB60856510NB (P)DFNB35 (AR)https://omim.org/allelicVariants/602167
ESPN60900610NB (P)DFNB36 (AR)https://omim.org/allelicVariants/606351
MYO6607821N/ADFNB37 (AR)https://omim.org/allelicVariants/600970
HGF608265N/ADFNB39 (AR)https://omim.org/allelicVariants/142409
ILDR160964610NB (P)DFNB42 (AR)https://omim.org/allelicVariants/609739
ADCY1610154N/ADFNB44 (AR)https://omim.org/allelicVariants/103072
CIB260943910NB (P)DFNB48 (AR)https://omim.org/allelicVariants/605564
MARVELD261015310NB (P)DFNB49 (AR)https://omim.org/allelicVariants/610572
COL11A2609706N/ADFNB53 (AR)https://omim.org/allelicVariants/120290
PDZD761800310NB (P)DFNB57 (AR)https://omim.org/allelicVariants/612971
PJVK61022010NB (P)DFNB59 (AR)https://omim.org/allelicVariants/610219
SLC26A5613865N/ADFNB61 (AR)https://omim.org/allelicVariants/604943
LRTOMT61145110NB (P)DFNB63 (AR)https://omim.org/allelicVariants/612414
DCDC2610212N/ADFNB66 (AR)https://omim.org/allelicVariants/605755
LHFPL561026510NB (P)DFNB67 (AR)https://omim.org/allelicVariants/609427
S1PR261041910NB (P)DFNB68 (AR)https://omim.org/allelicVariants/605111
PNPT1614934N/ADFNB70 (AR)https://omim.org/allelicVariants/610316
BSND602522N/ASensorineural deafness with mild renal dysfunction (AR)https://omim.org/allelicVariants/606412
MSRB3613718N/ADFNB74 (AR)https://omim.org/allelicVariants/613719
SYNE4615540N/ADFNB76 (AR)https://omim.org/allelicVariants/615535
LOXHD1613079N/ADFNB77 (AR)https://omim.org/allelicVariants/613072
TPRN61330710NB (P)DFNB79 (AR)https://omim.org/allelicVariants/613354
GPSM2604213N/ADFNB82 (AR)https://omim.org/allelicVariants/609245
PTPRQ61339110NB (P)DFNB84A (AR)https://omim.org/allelicVariants/603317
OTOGL61494410NB (P)DFNB84B (AR)https://omim.org/allelicVariants/614925
TBC1D24614617N/ADFNB86 (AR)https://omim.org/allelicVariants/613577
ELMOD3615429N/ADFNB88 (AR)https://omim.org/allelicVariants/615427
KARS (KARS1)613916N/ADFNB89 (AR)https://omim.org/allelicVariants/601421
SERPINB6613453N/ADFNB91 (AR)https://omim.org/allelicVariants/173321
CABP261489910NB (P)DFNB93 (AR)https://omim.org/allelicVariants/607314
NARS2618434N/ADFNB94 (AR)https://omim.org/allelicVariants/612803
MET616705N/ADFNB97 (AR)https://omim.org/allelicVariants/164860
TSPEAR614861N/ADFNB98 (AR)https://omim.org/allelicVariants/612920
TMEM132E618481N/ADFNB99 (AR)https://omim.org/allelicVariants/616178
PPIP5K2618422N/ADFNB100 (AR)https://omim.org/allelicVariants/611648
GRXCR2615837N/ADFNB101 (AR)https://omim.org/allelicVariants/615762
EPS8615974N/ADFNB102 (AR)https://omim.org/allelicVariants/600206
CLIC5616042N/ADFNB103 (AR)https://omim.org/allelicVariants/607293
RIPOR2616515N/ADFNB104 (AR)https://omim.org/allelicVariants/611410
EPS8L2617637N/ADFNB106 (AR)https://omim.org/allelicVariants/614988
WBP2617639N/ADFNB107 (AR)https://omim.org/allelicVariants/606962
ROR1617654N/ADFNB108 (AR)https://omim.org/allelicVariants/602336
ESRP1618013N/ADFNB109 (AR)https://omim.org/allelicVariants/612959
COCH618094N/ADFNB110 (AR)https://omim.org/allelicVariants/603196
MPZL2618145N/ADFNB111 (AR)https://omim.org/allelicVariants/604873
BDP1618257N/ADFNB112 (AR)https://omim.org/allelicVariants/607012
CEACAM16618410N/ADFNB113 (AR)https://omim.org/allelicVariants/614591
GRAP618456N/ADFNB114 (AR)https://omim.org/allelicVariants/604330
SPNS2618457N/ADFNB115 (AR)https://omim.org/allelicVariants/612584
KCNJ10600791N/AEnlarged vestibular aqueduct, digenic (AR)https://omim.org/allelicVariants/602208
FOXI1600791N/AEnlarged vestibular aqueduct (AR)https://omim.org/allelicVariants/601093
PRPS1304500N/ADFNX1 (XL)https://omim.org/allelicVariants/311850
POU3F430440010NB (P)DFNX2 (XLR)https://omim.org/allelicVariants/300039
SMPX300066N/ADFNX4 (XLD)https://omim.org/allelicVariants/300226
AIFM1300614N/ADFNX5 (XLR)https://omim.org/allelicVariants/300169
COL4A6300914N/ADFNX6 (XLR)https://omim.org/allelicVariants/303631
GPRASP2301018N/ADFNX7 (XLR)https://omim.org/allelicVariants/300969
*ClinGen Actionability Working GroupのSemi-quantitative Metric (SQM) scoring、Outcome/Intervention Pairに関する情報は https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/ を参照。
欧米人での遺伝子頻度

常染色体優性の症候性難聴において、Waardenburg症候群 (WS) I型とIII型ではPAX3、WSII型の一部の症例はMITF、WSIV型はEDNRB、EDN3、SOX10遺伝子の病的バリアントにより発症するが頻度情報の報告は見当たらない。鰓弓耳腎症候群の表現型が認められる家系の約40%でEYA1遺伝子の病的バリアントが確認される。Stickler症候群はCOL2A1、COL11A1、COL11A2遺伝子の病的バリアントにより発症し、神経繊線維腫症2型はNF2遺伝子変異により発症するが、いずれも頻度情報の報告は見当たらない。常染色体劣性の症候性難聴において、Pendred症候群では家系の約50%でSLC26A4遺伝子の病的バリアントが同定される。X連鎖性症候性難聴であるMohr-Tranebjaerg症候群の原因遺伝子はTIMM8Aであるが頻度情報の報告は見当たらない。非症候性難聴における遺伝子頻度は報告されていないようである(GeneReviewsより引用)。

日本人での遺伝子頻度

日本人の常染色体優性遺伝形式をとる感音性難聴患者75名に対して既知の難聴遺伝子の解析を行った結果、46名 (61.3%) に少なくとも1つの候補となる病的バリアントを認めたという報告がある (PLoS One. 2016. PMID: 27911912)。日本人先天性難聴患者のうち約20%にGJB2遺伝子の病的バリアントが見出され、一般健常者の保因者頻度が約1/50である。また、前庭水管拡大を伴う難聴症例の80-90%でSLC26A4遺伝子の病的バリアントが検出され、日本人先天性難聴患者のうち2番目に頻度が高い (小児科診療. 1123-1130. 2013)。

掲載日: 2019/10/10更新日: 2022/10/18